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Oral squamous cell carcinoma (OSCC) is worldwide health problem associated with high morbidity and mortality. From both the patient and socioeconomic perspectives, prevention of progression of premalignant oral intraepithelial neoplasia (OIN) to OSCC is clearly the preferable outcome. Optimal OSCC chemopreventives possess a variety of attributes including high tolerability, bioavailability, efficacy and preservation of an intact surface epithelium. Terminal differentiation, which directs oral keratinocytes leave the proliferative pool to form protective cornified envelopes, preserves the protective epithelial barrier while concurrently eliminating growth-aberrant keratinocytes. This study employed human premalignant oral keratinocytes and an OSCC cell line to evaluate the differentiation-inducing capacity of the synthetic retinoid, fenretinide (4HPR). Full-thickness oral mucosal explants were evaluated for proof of concept differentiation studies. Results of this study characterize the ability of 4HPR to fulfill all requisite components for keratinocyte differentiation, i.e. nuclear import via binding to cellular RA binding protein-II (molecular modeling), binding to and subsequent activation of retinoic acid nuclear receptors (receptor activation assays), increased expression and translation of genes associated with keratinocyte differentiation [Reverse transcription polymerase chain reaction (RT-PCR), immunoblotting] upregulation of a transglutaminase enzyme essential for cornified envelope formation (transglutaminase 3, functional assay) and augmentation of terminal differentiation in human oral epithelial explants (image-analyses quantified corneocyte desquamation). These data build upon the chemoprevention repertoire of 4HPR that includes function as a small molecule kinase inhibitor and inhibition of essential mechanisms necessary for basement membrane invasion. An upcoming clinical trial, which will assess whether a 4HPR-releasing mucoadhesive patch induces histologic, clinical and molecular regression in OIN lesions, will provide essential clinical insights. [ABSTRACT FROM AUTHOR]

Basement membrane invasion defines malignant transformation of surface premalignancy. Treatment of oral squamous cell carcinoma (OSCC) cells with the synthetic vitamin A derivative, fenretinide (4HPR), induces numerous cancer-preventive effects including suppression of basement membrane invasion, elimination of anchorage-independent growth, disruption of actin cytoskeletal components and inhibition of the invasion-enabling focal adhesive kinase. The purpose of this study was to elucidate 4HPR's effects on additional invasion-relevant mechanisms including matrix metalloproteinase (MMP) activation and function, cell–extracellular matrix (ECM) attachments and interaction with a kinase that is essential for the epithelial–myoepithelial transformation i.e. c-Jun NH2-terminal kinase (JNK). Our data revealed that 4HPR binds with high affinity to the ATP-binding site of all three JNK isoforms with concurrent suppression of kinase function. Additional studies showed 4HPR treatment inhibited both OSCC cell–ECM adhesion and MMP activation and function. JNK downregulation and induced expression studies confirmed that the JNK3 isoform conveyed that largest impact on OSCC migration and invasion. Biodegradable polymeric implants formulated to preserve 4HPR's function and bioavailability were employed to assess 4HPR's chemopreventive impact on an OSCC tumor induction model. These studies revealed 4HPR local delivery significantly inhibited OSCC tumor size, mitotic indices and expression of the endothelial marker, erythroblast transformation-specific-related gene with concurrent increases in tumor apoptosis (cleaved caspase-3). Collectively, these data show that 4HPR suppresses invasion at multiple sites including 'outside-in' signaling, cell–ECM interactions and suppression of MMPs. These functions are also essential for physiologic function. Regulation is therefore essential and reinforces the pharmacologic advantage of local delivery chemopreventive formulations.. [ABSTRACT FROM AUTHOR]

This study reported the reactivity and mechanisms of superoxide radical (O2˙−)-mediated transformation of pentachlorophenate. Our results indicated that O2˙− alone exhibits limited effects on its degradation, and bimolecular nucleophilic substitution is the dominant reaction pathway. [ABSTRACT FROM AUTHOR]

Transfer entropy (TE) is a widely used measure of directed information flows in a number of domains including neuroscience. Many real-world time series for which we are interested in information flows come in the form of (near) instantaneous events occurring over time. Examples include the spiking of biological neurons, trades on stock markets and posts to social media, amongst myriad other systems involving events in continuous time throughout the natural and social sciences. However, there exist severe limitations to the current approach to TE estimation on such event-based data via discretising the time series into time bins: it is not consistent, has high bias, converges slowly and cannot simultaneously capture relationships that occur with very fine time precision as well as those that occur over long time intervals. Building on recent work which derived a theoretical framework for TE in continuous time, we present an estimation framework for TE on event-based data and develop a k-nearest-neighbours estimator within this framework. This estimator is provably consistent, has favourable bias properties and converges orders of magnitude more quickly than the current state-of-the-art in discrete-time estimation on synthetic examples. We demonstrate failures of the traditionally-used source-time-shift method for null surrogate generation. In order to overcome these failures, we develop a local permutation scheme for generating surrogate time series conforming to the appropriate null hypothesis in order to test for the statistical significance of the TE and, as such, test for the conditional independence between the history of one point process and the updates of another. Our approach is shown to be capable of correctly rejecting or accepting the null hypothesis of conditional independence even in the presence of strong pairwise time-directed correlations. This capacity to accurately test for conditional independence is further demonstrated on models of a spiking neural circuit inspired by the pyloric circuit of the crustacean stomatogastric ganglion, succeeding where previous related estimators have failed. Author summary: Transfer Entropy (TE) is an information-theoretic measure commonly used in neuroscience to measure the directed statistical dependence between a source and a target time series, possibly also conditioned on other processes. Along with measuring information flows, it is used for the inference of directed functional and effective networks from time series data. The currently-used technique for estimating TE on neural spike trains first time-discretises the data and then applies a straightforward plug-in information-theoretic estimation procedure. This approach has numerous drawbacks: it has high bias, cannot capture relationships occurring on both fine and large timescales simultaneously, converges very slowly as more data is obtained, and indeed does not even converge to the correct value for any practical non-vanishing discretisation scale. We present a new estimator for TE which operates in continuous time and demonstrate, via application to synthetic examples, that it addresses these problems and can reliably differentiate statistically significant flows from (conditionally) independent spike trains. Further, we also apply it to more biologically-realistic spike trains obtained from a biophysical model inspired by the pyloric circuit of the crustacean stomatogastric ganglion; our correct inference of directed conditional dependence and independence between neurons here provides an important validation for our approach where similar methods have previously failed. [ABSTRACT FROM AUTHOR]

Understanding the impact of behavior dependent mobility in the spread of epidemics and social disorders is an outstanding problem in computational epidemiology. We present a modelling approach for the study of mobility that adapts dynamically according to individual state, epidemic/social-contagion state and network topology in accordance with limited data and/or common behavioral models. We demonstrate that even for simple compartmental network processes, our approach leads to complex spatial patterns of infection in the endemic state dependent on individual behavior. Specifically, we characterize the resulting phenomena in terms of phase separation, highlighting phase transitions between distinct spatial states and determining the systems' phase diagram. The existence of such phases implies that small changes in the populations' perceptions could lead to drastic changes in the spatial extent and morphology of the epidemic/social phenomena. [ABSTRACT FROM AUTHOR]

In this study, we investigated the removal efficiency of an anti-inflammatory analgesic compound ibuprofen (IBU) in a UV/persulfate system under various environmentally relevant conditions. The effects of water matrix, including natural organic matter (NOM), sulfate anion (SO4²-), nitrate anion (NO3 -) and chloride anion (Cl-) were evaluated. Our results showed that the degradation kinetics of IBU was significantly enhanced in the presence of persulfate and the dominant degradation pathway was determined to be via sulfate radical anion (SO4•-) oxidation. The second order rate constant of IBU reacting with SO4 •-was determined to be (1.26 ± 0.09) × 109 M-1 s-1 at pH = 7.55. The observed pseudo first-order rate constants for IBU degradation (kobs) increased with the persulfate dosage, but it significantly decreased in the presence of NOM. The presence of SO4²- and NO3 - did not exhibit impact on the degradation of IBU, but the kobs values slightly decreased by about 15% in the presence of 5 mM Cl-. The inhibition effect of Cl- might be due to secondary chlorine-derived radicals competing for SO4 •-, resulting in a reduced IBU degradation kinetics. [ABSTRACT FROM AUTHOR]

An increasing number of organic compounds are manufactured, consumed, and discarded every year. Incomplete destruction of these compounds in wastewater treatment plants leads to pollution of natural waters, posing great health and ecological concerns. Ultrasound, as an emerging advanced oxidation technology, can quickly and effectively degrade organic pollutants in waters. To improve removal efficiency of organic pollutants in an ultrasonic system, operational parameters, especially pH, have been frequently evaluated and optimized. This review show that pH-induced changes in volatility, hydrophobicity and Coulombic force between the target compound and cavitation bubbles leads to higher degradation at acidic pH for most compounds. In addition, pH also changes free radical formation and reactivity in water during sonication, thereby altering degradation kinetics of target compounds. However, the influence of pH is not always consistent for various organic pollutants covering a broad range of physicochemical properties and reactivities. A systematic investigation on the pH effect is necessary to elucidate how pH alters cavitation bubble dynamics and collapse, radical yield and reactivity, distribution of target compounds in the vicinity of cavitation bubbles, water matrices transformation, and ultimately the degradation kinetics of organic pollutants. This first systematic review provides valuable insight into the pH effects on organic pollutant sonolysis, helps to improve our mechanistic understanding of the sonochemical system, and sheds light on future application of ultrasound in water engineering. [ABSTRACT FROM AUTHOR]

Little is known of the patterns of physical activity, standing and sitting by office workers. However, insight into these behaviours is of growing interest, notably in regard to public health priorities to reduce non-communicable disease risk factors associated with high levels of sitting time and low levels of physical activity. With the advent and increasing availability of indoor tracking systems it is now becoming possible to build detailed pictures of the usage of indoor spaces. This paper reports initial results of indoor tracking used in conjunction with the ActivPAL activity monitoring device. In this paper we give an overview of the usage of the tracking system and its installation and illustrate some of the resultant data. We also provide preliminary results that investigate the relationship between location, light physical activity and sitting in a small sample of office workers (n=33) from two separate office environments in order to demonstrate the relevance and explanatory power of the technique. [ABSTRACT FROM AUTHOR]

Ibuprofen, a frequently detected pharmaceutical in natural and engineered waters, was studied in both neutral and anionic forms using density functional theory at the B3LYP/6-311++G**//B3LYP/6-31G* level of theory in its reaction with hydroxyl radical ( •OH). The reaction pathways included •OH addition to aromatic ring, abstraction of a H-atom, and nucleophilic attack on the carbonyl group. The results showed that H-atom abstraction pathways are the most favorable. The free energy change for H-atom abstraction reaction ranges from −37.8 to −15.9 kcal/mol; for •OH addition ranges from −3.85 to −1.23 kcal/mol; and for nucleophilic attack on the carbonyl group is 13.9 kcal/mol. The calculated rate constant between neutral ibuprofen and •OH, 6.72 × 109 M−1s−1, is consistent with the experimental value, 6.5 ± 0.2 × 109 M−1s−1. Our results provide direct evidence for byproduct formation and identification on the molecular level. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Introduction: Health benefits of regular participation in physical activity are well documented but population levels are low. Office layout, and in particular the number and location of office building destinations (eg, print and meeting rooms), may influence both walking time and characteristics of sitting time. No research to date has focused on the role that the layout of the indoor office environment plays in facilitating or inhibiting step counts and characteristics of sitting time. The primary aim of this study was to investigate associations between office layout and physical activity, as well as sitting time using objective measures. Methods and analysis: Active buildings is a unique collaboration between public health, built environment and computer science researchers. The study involves objective monitoring complemented by a larger questionnaire arm. UK office buildings will be selected based on a variety of features, including office floor area and number of occupants. Questionnaires will include items on standard demographics, well-being, physical activity behaviour and putative socioecological correlates of workplace physical activity. Based on survey responses, approximately 30 participants will be recruited from each building into the objective monitoring arm. Participants will wear accelerometers (to monitor physical activity and sitting inside and outside the office) and a novel tracking device will be placed in the office (to record participant location) for five consecutive days. Data will be analysed using regression analyses, as well as novel agent-based modelling techniques. Ethics and dissemination: The results of this study will be disseminated through peer-reviewed publications and scientific presentations. Ethical approval was obtained through the University College London Research Ethics Committee (Reference number 4400/001). [ABSTRACT FROM AUTHOR]

We investigated phase transitions in spatial connectivity during influenza pandemics, relating epidemic thresholds to the formation of clusters defined in terms of average infection. We employed a large-scale agent-based model of influenza spread at a national level: the Australian Census-based Epidemic Model (AceMod). In using the AceMod simulation framework, which leverages the 2016 Australian census data and generates a surrogate population of ≈23.4 million agents, we analysed the spread of simulated epidemics across geographical regions defined according to the Australian Statistical Geography Standard. We considered adjacent geographic regions with above average prevalence to be connected, and the resultant spatial connectivity was then analysed at specific time points of the epidemic. Specifically, we focused on the times when the epidemic prevalence peaks, either nationally (first wave) or at a community level (second wave). Using the percolation theory, we quantified the connectivity and identified critical regimes corresponding to abrupt changes in patterns of the spatial distribution of infection. The analysis of criticality is confirmed by computing Fisher Information in a model-independent way. The results suggest that the post-critical phase is characterised by different spatial patterns of infection developed during the first or second waves (distinguishing urban and rural epidemic peaks). [ABSTRACT FROM AUTHOR]