Rapid production of block copolymer nano-objects via continuous-flow ultrafast RAFT dispersion polymerisation

Ultrafast RAFT polymerisation is exploited under dispersion polymerisation conditions for the synthesis of poly(dimethylacrylamide)-b-poly(diacetoneacrylamide) (PDMAmx-b-PDAAmy) diblock copolymer nanoparticles. This process is conducted within continuous-flow reactors, which are well suited to fast reactions and can easily dissipate exotherms making the process potentially scalable. Transient kinetic profiles obtained in-line via low-field flow nuclear magnetic resonance spectroscopy (flow-NMR) confirmed the rapid rate of polymerisation whilst still maintaining pseudo first order kinetics. Gel permeation chromatography (GPC) reported molar mass dispersities, Đ < 1.3 for a series of PDMAmx-b-PDAAmy diblock copolymers (x = 46, or 113; y = 50, 75, 100, 150 and 200) confirming control over molecular weight was maintained. Particle characterisation by dynamic light scattering (DLS) and transmission electron microscopy (TEM) indicated successful preparation of spheres and a majority worm phase at 90 °C but the formation of vesicular morphologies was only possible at 70 °C. To maintain the rapid rate of reaction at this lower temperature, initiator concentration was increased which was also required to overcome the gradual ingress of oxygen into the PFA tubing which was quenching the reaction at low radical concentrations. Illdefined morphologies observed at PDAAm DPs close to the worm-vesicle boundary, combined with a peak in molar mass dispersity suggested poor mixing prevented an efficient morphological transition for these samples. However, by targeting higher PDAAm DPs, the additional monomer present during the transition plasticises the chains to facilitate formation of vesicles at PDAAm DPs of ≥300

Urinary, bowel and sexual symptoms in a cohort of patients with Friedreich's ataxia

BACKGROUND: Pelvic symptoms are distressing symptoms experienced by patients with Friedreich’s Ataxia (FRDA). The aim of this study was to describe the prevalence of lower urinary tract symptoms (LUTS), bowel and sexual symptoms in FRDA. METHODS: Questionnaire scores measuring LUTS, bowel and sexual symptoms were analysed with descriptive statistics as a cohort and as subgroups (Early/Late-onset and Early/Late-stage FRDA) They were also correlated with validated measures of disease severity including those of ataxia severity, non-ataxic symptoms and activities of daily living. RESULTS: 80% (n = 46/56) of patients reported LUTS, 64% (n = 38/59) reported bowel symptoms and 83% (n = 30/36) reported sexual symptoms. Urinary and bowel or sexual symptoms were significantly likely to co-exist among patients. Late-onset FRDA patients were also more likely to report LUTS than early-onset ones. Patients with a longer disease duration reported higher LUTS scores and poorer quality of life scores related to urinary symptoms. CONCLUSIONS: A high proportion of FRDA have symptoms suggestive of LUTS, bowel and sexual dysfunction. This is more marked with greater disease duration and later disease onset. These symptoms need to be addressed by clinicians as they can have a detrimental effect on patients

Inhibition of Hippocampal Synaptic Activity by ATP, Hypoxia or Oxygen-Glucose Deprivation Does Not Require CD73

Adenosine, through activation of its A1 receptors, has neuroprotective effects during hypoxia and ischemia. Recently, using transgenic mice with neuronal expression of human equilibrative nucleoside transporter 1 (hENT1), we reported that nucleoside transporter-mediated release of adenosine from neurons was not a key mechanism facilitating the actions of adenosine at A1 receptors during hypoxia/ischemia. The present study was performed to test the importance of CD73 (ecto-5′-nucleotidase) for basal and hypoxic/ischemic adenosine production. Hippocampal slice electrophysiology was performed with CD73+/+ and CD73−/− mice. Adenosine and ATP had similar inhibitory effects in both genotypes, with IC50 values of approximately 25 µM. In contrast, ATP was a less potent inhibitor (IC50 = 100 µM) in slices from mice expressing hENT1 in neurons. The inhibitory effects of ATP in CD73+/+ and CD73−/− slices were blocked by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) and were enhanced by the nucleoside transport inhibitor S-(4-nitrobenzyl)-6-thioinosine (NBTI), consistent with effects that are mediated by adenosine after metabolism of ATP. AMP showed a similar inhibitory effect to ATP and adenosine, indicating that the response to ATP was not mediated by P2 receptors. In comparing CD73−/− and CD73+/+ slices, hypoxia and oxygen-glucose deprivation produced similar depression of synaptic transmission in both genotypes. An inhibitor of tissue non-specific alkaline phosphatase (TNAP) was found to attenuate the inhibitory effects of AMP and ATP, increase basal synaptic activity and reduce responses to oxygen-glucose deprivation selectively in slices from CD73−/− mice. These results do not support an important role for CD73 in the formation of adenosine in the CA1 area of the hippocampus during basal, hypoxic or ischemic conditions, but instead point to TNAP as a potential source of extracellular adenosine when CD73 is absent

Patient ratings in exercise therapy for the management of tendinopathy: a systematic review with meta-analysis.

The objective of this study was to synthesise exercise therapy intervention data investigating patient rating outcomes for the management of tendinopathy. A systematic review and meta-analysis of randomised controlled trials investigating exercise therapy interventions and reporting patient rating outcomes were undertaken. Eligible settings were considered to be any setting in any country listed as very high on the human development index. Eligible participants were considered to be people with a diagnosis of any tendinopathy of any severity or duration. Exercise therapy for the management of tendinopathy was considered for inclusion based on alignment with five different therapy classes: 1) resistance; 2) plyometric; 3) vibration; 4) flexibility; and 5) movement pattern retraining modalities. The main outcomes sought were those that measured patient rating of condition, including patient satisfaction and Global Rating of Change (GROC). From a total of 124 exercise therapy studies, 34 (Achilles: 41%; rotator cuff: 32%; patellar: 15%; elbow: 9%; and gluteal: 3%) provided sufficient information to be meta-analysed. The data were obtained across 48 treatment arms and 1246 participants. The pooled estimate for proportion of satisfaction was 0.63 [95% CrI: 0.53 to 0.73], and the pooled estimate for percentage of maximum GROC was 53 [95% CrI: 38 to 69%]. The proportion of patients reporting positive satisfaction and perception of change increased with longer follow-up periods from treatment onset. Patient satisfaction and GROC appear similar and are ranked moderately high demonstrating that patients generally perceive exercise therapies positively. Further research including greater consistency in measurement tools is required to explore and where possible, identify patient- and exercise-related moderating factors that can be used to improve person-centred care

Role of the mesoamygdaloid dopamine projection in emotional learning

Amygdala dopamine is crucially involved in the acquisition of Pavlovian associations, as measured via conditioned approach to the location of the unconditioned stimulus (US). However, learning begins before skeletomotor output, so this study assessed whether amygdala dopamine is also involved in earlier 'emotional' learning. A variant of the conditioned reinforcement (CR) procedure was validated where training was restricted to curtail the development of selective conditioned approach to the US location, and effects of amygdala dopamine manipulations before training or later CR testing assessed. Experiment 1a presented a light paired (CS+ group) or unpaired (CS- group) with a US. There were 1, 2 or 10 sessions, 4 trials per session. Then, the US was removed, and two novel levers presented. One lever (CR+) presented the light, and lever pressing was recorded. Experiment 1b also included a tone stimulus. Experiment 2 applied intra-amygdala R(+) 7-OH-DPAT (10 nmol/1.0 A mu l/side) before two training sessions (Experiment 2a) or a CR session (Experiment 2b). For Experiments 1a and 1b, the CS+ group preferred the CR+ lever across all sessions. Conditioned alcove approach during 1 or 2 training sessions or associated CR tests was low and nonspecific. In Experiment 2a, R(+) 7-OH-DPAT before training greatly diminished lever pressing during a subsequent CR test, preferentially on the CR+ lever. For Experiment 2b, R(+) 7-OH-DPAT infusions before the CR test also reduced lever pressing. Manipulations of amygdala dopamine impact the earliest stage of learning in which emotional reactions may be most prevalent

Beyond element-wise interactions: identifying complex interactions in biological processes

Background: Biological processes typically involve the interactions of a number of elements (genes, cells) acting on each others. Such processes are often modelled as networks whose nodes are the elements in question and edges pairwise relations between them (transcription, inhibition). But more often than not, elements actually work cooperatively or competitively to achieve a task. Or an element can act on the interaction between two others, as in the case of an enzyme controlling a reaction rate. We call “complex” these types of interaction and propose ways to identify them from time-series observations. Methodology: We use Granger Causality, a measure of the interaction between two signals, to characterize the influence of an enzyme on a reaction rate. We extend its traditional formulation to the case of multi-dimensional signals in order to capture group interactions, and not only element interactions. Our method is extensively tested on simulated data and applied to three biological datasets: microarray data of the Saccharomyces cerevisiae yeast, local field potential recordings of two brain areas and a metabolic reaction. Conclusions: Our results demonstrate that complex Granger causality can reveal new types of relation between signals and is particularly suited to biological data. Our approach raises some fundamental issues of the systems biology approach since finding all complex causalities (interactions) is an NP hard problem

Discovering study-specific gene regulatory networks

This article has been made available through the Brunel Open Access Publishing Fund.Microarrays are commonly used in biology because of their ability to simultaneously measure thousands of genes under different conditions. Due to their structure, typically containing a high amount of variables but far fewer samples, scalable network analysis techniques are often employed. In particular, consensus approaches have been recently used that combine multiple microarray studies in order to find networks that are more robust. The purpose of this paper, however, is to combine multiple microarray studies to automatically identify subnetworks that are distinctive to specific experimental conditions rather than common to them all. To better understand key regulatory mechanisms and how they change under different conditions, we derive unique networks from multiple independent networks built using glasso which goes beyond standard correlations. This involves calculating cluster prediction accuracies to detect the most predictive genes for a specific set of conditions. We differentiate between accuracies calculated using cross-validation within a selected cluster of studies (the intra prediction accuracy) and those calculated on a set of independent studies belonging to different study clusters (inter prediction accuracy). Finally, we compare our method's results to related state-of-the art techniques. We explore how the proposed pipeline performs on both synthetic data and real data (wheat and Fusarium). Our results show that subnetworks can be identified reliably that are specific to subsets of studies and that these networks reflect key mechanisms that are fundamental to the experimental conditions in each of those subsets

A Minimal Model of Metabolism Based Chemotaxis

Since the pioneering work by Julius Adler in the 1960's, bacterial chemotaxis has been predominantly studied as metabolism-independent. All available simulation models of bacterial chemotaxis endorse this assumption. Recent studies have shown, however, that many metabolism-dependent chemotactic patterns occur in bacteria. We hereby present the simplest artificial protocell model capable of performing metabolism-based chemotaxis. The model serves as a proof of concept to show how even the simplest metabolism can sustain chemotactic patterns of varying sophistication. It also reproduces a set of phenomena that have recently attracted attention on bacterial chemotaxis and provides insights about alternative mechanisms that could instantiate them. We conclude that relaxing the metabolism-independent assumption provides important theoretical advances, forces us to rethink some established pre-conceptions and may help us better understand unexplored and poorly understood aspects of bacterial chemotaxis