The success of shape optimisation depends significantly on the parametrisation of the shape. Ideally, it defines a very rich variation in shape, allows for rapid grid generation of high quality, and expresses the shape in a standard Computer Aided Design (CAD) representation. While most existing parametrisation methods fail at least one of these criteria, this work introduces a novel parametrisation method, which satisfies all three. A tri-variate B-spline volume is used to define the volume to be optimised. The position of the external control points are used as design parameters, while the internal control points are repositioned to ensure regularity of the transformation. The grid generation process transforms a Cartesian grid (defined in parametric space) to the physical space using the tri-variate net of control points. This process guarantees a high grid quality even for large deformations, and has extremely low computational cost as it only involves a transformation from parameter space to physical space. This allows the computation of the grid sensitivities with respect to the design variables at a fraction of the cost of a Computational Fluid Dynamics (CFD) iteration, therefore allowing the use of one-shot methods. This novel parametrisation is applied to the shape optimisation of a U-bend passage of a turbine-blade serpentine-cooling channel with the objective to minimise pressure losses. A steady state, Reynolds-Averaged, density-based Navier-Stokes solver is used to predict the pressure losses at a Reynolds number of 40,000. The sensitivities of the objective function with respect to the control points are computed using a hand-derived adjoint solver and geometry generation system. A one-shot approach is used to simultaneously converge flow, gradient and design, resulting in a rapid design approach with a design time equivalent to approximately 10 normal CFD runs, while still maintaining a CAD representation of the geometry. A large reduction in pressure loss is obtained, and the flow in the optimal geometry is analysed in detail. Full article

Mitochondria are the repository for various metabolites involved in diverse energy-generating processes, like the TCA cycle, oxidative phosphorylation, and metabolism of amino acids, fatty acids, and nucleotides, which rely significantly on flavoenzymes, such as oxidases, reductases, and dehydrogenases. Flavoenzymes are functionally dependent on biologically active flavin adenine dinucleotide (FAD) or flavin mononucleotide (FMN), which are derived from the dietary component riboflavin, a water soluble vitamin. Riboflavin regulates the structure and function of flavoenzymes through its cofactors FMN and FAD and, thus, protects the cells from oxidative stress and apoptosis. Hence, it is not surprising that any disturbance in riboflavin metabolism and absorption of this vitamin may have consequences on cellular FAD and FMN levels, resulting in mitochondrial dysfunction by reduced energy levels, leading to riboflavin associated disorders, like cataracts, neurodegenerative and cardiovascular diseases, etc. Furthermore, mutations in either nuclear or mitochondrial DNA encoding for flavoenzymes and flavin transporters significantly contribute to the development of various neurological disorders. Moreover, recent studies have evidenced that riboflavin supplementation remarkably improved the clinical symptoms, as well as the biochemical abnormalities, in patients with neuronopathies, like Brown-Vialetto-Van-Laere syndrome (BVVLS) and Fazio-Londe disease. This review presents an updated outlook on the cellular and molecular mechanisms of neurodegenerative disorders in which riboflavin deficiency leads to dysfunction in mitochondrial energy metabolism, and also highlights the significance of riboflavin supplementation in aforementioned disease conditions. Thus, the outcome of this critical assessment may exemplify a new avenue to enhance the understanding of possible mechanisms in the progression of neurodegenerative diseases and may provide new rational approaches of disease surveillance and treatment. Full article

Despite significant advances in the last three decades towards high yielding syntheses of rotaxanes, the preparation of systems constructed from more than two components remains a challenge. Herein we build upon our previous report of an active template copper-catalyzed azide-alkyne cycloaddition (CuAAC) rotaxane synthesis with a diyne in which, following the formation of the first mechanical bond, the steric bulk of the macrocycle tempers the reactivity of the second alkyne unit. We have now extended this approach to the use of 1,3,5-triethynylbenzene in order to successively prepare [2]-, [3]- and [4]rotaxanes without the need for protecting group chemistry. Whilst the first two iterations proceeded in good yield, the steric shielding that affords this selectivity also significantly reduces the efficacy of the active template (AT)-CuAAC reaction of the third alkyne towards the preparation of [4]rotaxanes, resulting in severely diminished yields. Full article

Our objective was to model the average wood density in black spruce trees in representative stands across a boreal forest landscape based on relationships with predictor variables extracted from airborne light detection and ranging (LiDAR) point cloud data. Increment core samples were collected from dominant or co-dominant black spruce trees in a network of 400 m² plots distributed among forest stands representing the full range of species composition and stand development across a 1,231,707 ha forest management unit in northeastern Ontario, Canada. Wood quality data were generated from optical microscopy, image analysis, X-ray densitometry and diffractometry as employed in SilviScan™. Each increment core was associated with a set of field measurements at the plot level as well as a suite of LiDAR-derived variables calculated on a 20 × 20 m raster from a wall-to-wall coverage at a resolution of ~1 point m⁻². We used a multiple linear regression approach to identify important predictor variables and describe relationships between stand structure and wood density for average black spruce trees in the stands we observed. A hierarchical classification model was then fitted using random forests to make spatial predictions of mean wood density for average trees in black spruce stands. The model explained 39 percent of the variance in the response variable, with an estimated root mean square error of 38.8 (kg·m⁻³). Among the predictor variables, P20 (second decile LiDAR height in m) and quadratic mean diameter were most important. Other predictors describing canopy depth and cover were of secondary importance and differed according to the modeling approach. LiDAR-derived variables appear to capture differences in stand structure that reflect different constraints on growth rates, determining the proportion of thin-walled earlywood cells in black spruce stems, and ultimately influencing the pattern of variation in important wood quality attributes such as wood density. A spatial characterization of variation in a desirable wood quality attribute, such as density, enhances the possibility for value chain optimization, which could allow the forest industry to be more competitive through efficient planning for black spruce management by including an indication of suitability for specific products as a modeled variable derived from standard inventory data. Full article

Protein is important to the human body, and different sources of protein may have different effects on the risk of breast cancer. Thus, we conducted a meta-analysis to investigate the association between different dietary protein sources and breast cancer risk. PubMed and several databases were searched until December 2015. Relevant articles were retrieved according to specific searching criteria. Forty-six prospective studies were included. The summary relative risk (RR) for highest versus lowest intake was 1.07 (95% confidence interval (CI) 1.01–1.14, I² = 34.6%) for processed meat, 0.92 (95% CI 0.84–1.00, I² = 0%) for soy food, 0.93 (95% CI 0.85–1.00, I² = 40.1%) for skim milk, and 0.90 (95% CI 0.82–1.00, I² = 0%) for yogurt. Similar conclusions were obtained in dose-response association for each serving increase: total red meat (RR: 1.07; 95% CI 1.01–1.14, I² = 7.1%), fresh red meat (RR: 1.13; 95% CI 1.01–1.26, I² = 56.4%), processed meat (RR: 1.09; 95% CI 1.02–1.17, I² = 11.8%), soy food (RR: 0.91; 95% CI 0.84–1.00, I² = 0%), and skim milk (RR: 0.96; 95% CI 0.92–1.00, I² = 11.9%). There was a null association between poultry, fish, egg, nuts, total milk, and whole milk intake and breast cancer risk. Higher total red meat, fresh red meat, and processed meat intake may be risk factors for breast cancer, whereas higher soy food and skim milk intake may reduce the risk of breast cancer. Full article

Tourette syndrome (TS) is a childhood neurobehavioural disorder, characterised by the presence of motor and vocal tics, typically starting in childhood but persisting in around 20% of patients into adulthood. In those patients who do not respond to pharmacological or behavioural therapy, deep brain stimulation (DBS) may be a suitable option for potential symptom improvement. This manuscript attempts to summarise the outcomes of DBS at different targets, explore the possible mechanisms of action of DBS in TS, as well as the potential of adaptive DBS. There will also be a focus on the future challenges faced in designing optimized trials. Full article

Postprandial hypotension (PPH), a fall in systolic blood pressure (SBP) within 2 h of a meal, may detrimentally affect gait parameters and increase the falls risk in older people. We aimed to determine the effects of postprandial SBP on heart rate (HR), gait speed, and stride length, double-support time and swing time variability in older subjects with and without PPH. Twenty-nine subjects were studied on three days: glucose (“G”), water and walk (“WW”), glucose and walk (“GW”). Subjects consumed a glucose drink on “G” and “GW” and water on “WW”. The “G” day determined which subjects had PPH. On “WW” and “GW” gait was analyzed. Sixteen subjects demonstrated PPH. In this group, there were significant changes in gait speed (p = 0.040) on “WW” and double-support time variability (p = 0.027) on “GW”. The area under the curve for the change in gait parameters from baseline was not significant on any study day. Among subjects without PPH, SBP increased on “WW” (p < 0.005) and all gait parameters remained unchanged on all study days. These findings suggest that by changing gait parameters, PPH may contribute to an increased falls risk in the older person with PPH. Full article

Myelodysplastic syndrome (MDS) is a group of heterogeneous clonal hematopoietic stem cell disorders characterized by cytopenia, ineffective hematopoiesis, and progression to secondary acute myeloid leukemia in high-risk cases. Conventional prognostication relies on clinicopathological parameters supplemented by cytogenetic information. However, recent studies have shown that genetic aberrations also have critical impacts on treatment outcome. Moreover, these genetic alterations may themselves be a target for treatment. The mutation landscape in MDS is shaped by gene aberrations involved in DNA methylation (TET2, DNMT3A, IDH1/2), histone modification (ASXL1, EZH2), the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, U2AF1/2), transcription (RUNX1, TP53, BCOR, PHF6, NCOR, CEBPA, GATA2), tyrosine kinase receptor signaling (JAK2, MPL, FLT3, GNAS, KIT), RAS pathways (KRAS, NRAS, CBL, NF1, PTPN11), DNA repair (ATM, BRCC3, DLRE1C, FANCL), and cohesion complexes (STAG2, CTCF, SMC1A, RAD21). A detailed understanding of the pathogenetic mechanisms leading to transformation is critical for designing single-agent or combinatorial approaches in target therapy of MDS. Full article

A composite metal oxide semiconductor (MOS) sensor array based on tin dioxide (SNO₂) and zinc oxide (ZnO) has been fabricated using a straight forward mechanical mixing method. The array was characterized using X-ray photoelectron spectroscopy, scanning electron microscopy, Raman spectroscopy and X-ray diffraction. The array was evaluated against a number of environmentally important reducing and oxidizing gases across a range of operating temperatures (300–500 °C). The highest response achieved was against 100 ppm ethanol by the 50 wt% ZnO–50 wt% SnO₂ device, which exhibited a response of 109.1, a 4.5-fold increase with respect to the pure SnO₂ counterpart (which displayed a response of 24.4) and a 12.3-fold enhancement with respect to the pure ZnO counterpart (which was associated with a response of 8.9), towards the same concentration of the analyte. Cross sensitivity studies were also carried out against a variety of reducing gases at an operating temperature of 300 °C. The sensors array showed selectivity towards ethanol. The enhanced behaviour of the mixed oxide materials was influenced by junction effects, composition, the packing structure and the device microstructure. The results show that it is possible to tune the sensitivity and selectivity of a composite sensor, through a simple change in the composition of the composite. Full article

Objective of this study was to evaluate the effect of different controlled release fertilizer technologies on nutrient leaching and plant growth parameters of two palm species, Chinese Fan (Livistona chinensis) and Queen (Syagrus romanzoffiana). We compared Nutri-Pak (12-4-12 controlled release packet) and Harrell’s (12-4-12 controlled release polymer coated urea) against Atlantic (8-4-12 controlled release polymer coated urea, coated sulfate of potash), the most commonly used palm fertilizer in South Florida. Plants were grown in 25 cm (11 L) pots under 70% shade, watered weekly, with pest and weed control done as required. Plant growth parameters: number of leaves, leaf length and width, and basal diameter, were measured every two months. Leachate was collected weekly after irrigation and a two-month composite sample was analyzed for nutrient concentrations. There was no difference in the growth parameters among the three fertilizers for Chinese Fan plants. However for Queen, Atlantic and Harrell’s had significantly thicker basal diameter than Nutri-Pak. Significant difference in the concentration of nutrients in the leachate was observed among the fertilizer types. Throughout the study period, Nutri-Pak had a lower concentration of nutrients in the leachate than Atlantic and Harrell’s. Our research indicates that Nutri-Pak control release fertilizer is comparable to other commercial fertilizers in Chinese Fan growth, but the larger Queen palms likely require an additional packet. Nutri-Pak fertilizer resulted in less nutrient leaching and could be a better environmental choice. Full article

Airborne Laser Scanning (ALS) metrics have been used to develop area-based forest inventories; these metrics generally include estimates of stand-level, per hectare values and mean tree attributes. Tree-based ALS inventories contain desirable information on individual tree dimensions and how much they vary within a stand. Adding size class distribution information to area-based inventories helps to bridge the gap between area- and tree-based inventories. This study examines the potential of ALS and stereo-imagery point clouds to predict size class distributions in a boreal forest. With an accurate digital terrain model, both ALS and imagery point clouds can be used to estimate size class distributions with comparable accuracy. Nonparametric imputations were generally superior to parametric imputations; this may be related to the limitation of using a unimodal Weibull function on a relatively small prediction unit (e.g., 400 m²). Full article

In dynamic environments, when faced with a choice of which learning strategy to adopt, do people choose to mostly explore (maximizing their long term gains) or exploit (maximizing their short term gains)? More to the point, how does this choice of learning strategy influence one’s later ability to control the environment? In the present study, we explore whether people’s self-reported learning strategies and levels of arousal (i.e., surprise, stress) correspond to performance measures of controlling a Highly Uncertain or Moderately Uncertain dynamic environment. Generally, self-reports suggest a preference for exploring the environment to begin with. After which, those in the Highly Uncertain environment generally indicated they exploited more than those in the Moderately Uncertain environment; this difference did not impact on performance on later tests of people’s ability to control the dynamic environment. Levels of arousal were also differentially associated with the uncertainty of the environment. Going beyond behavioral data, our model of dynamic decision-making revealed that, in actual fact, there was no difference in exploitation levels between those in the highly uncertain or moderately uncertain environments, but there were differences based on sensitivity to negative reinforcement. We consider the implications of our findings with respect to learning and strategic approaches to controlling dynamic uncertainty. Full article

A major aim of the international community is to decarbonize the economy. With renewables, international trade in energy is likely to increase. In turn, the international trading system can be a major vehicle towards moving away from fossil fuels to renewable energy. To this end, it can provide fair competition, economies of scale and knowledge transfer. This article analyzes the impact of European Union (EU) preferential trade agreements (PTAs) in addressing climate change mitigation and energy security by promoting renewables. Currently, there is a proliferation of PTAs; this trend seems irreversible and is likely to persist, given the current crisis in the multilateral trading system. We argue that the EU can, through its network of PTAs, move towards greater energy independence as renewable energy becomes increasingly economically viable. This article provides a thorough review of the renewable energy-related provisions in the EU’s current PTAs and recommends three tangible ways through which the EU could capitalize its vast network of PTAs to boost the renewable energy market. Full article

Ethnicity and race are often used interchangeably in the literature. However, the traditional definition of race and ethnicity is related to biological (bone structure and skin, hair, or eye color) and sociological factors (nationality, regional culture, ancestry, and language) respectively. Diabetes mellitus (DM) is a huge global public health problem. As the number of individuals with Type 2 DM grows, the prevalence of diabetic kidney disease (DKD), which is one of the most serious complications, is expected to rise sharply. Many ethnic and racial groups have a greater risk of developing DM and its associated macro and micro-vascular complications. Full article

Long non-coding RNAs (LncRNAs) represent a novel class of RNAs with no functional protein-coding ability, yet it has become increasingly clear that interactions between lncRNAs with other molecules are responsible for important gene regulatory functions in various contexts. Given their relatively high expressions in the brain, lncRNAs are now thought to play important roles in normal brain development as well as diverse disease processes including gliomagenesis. Intriguingly, certain lncRNAs are closely associated with the initiation, differentiation, progression, recurrence and stem-like characteristics in glioma, and may therefore be exploited for the purposes of sub-classification, diagnosis and prognosis. LncRNAs may also serve as potential therapeutic targets as well as a novel biomarkers in the treatment of glioma. In this article, the functional aspects of lncRNAs, particularly within the central nervous system (CNS), will be briefly discussed, followed by highlights of the important roles of lncRNAs in mediating critical steps during glioma development. In addition, the key lncRNA players and their possible mechanistic pathways associated with gliomagenesis will be addressed. Full article

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in many age groups. Neuroendocrine dysfunction has been recognized as a consequence of TBI and consists of both anterior and posterior pituitary insufficiency; water and electrolyte abnormalities (diabetes insipidus (DI) and the syndrome of inappropriate antidiuretic hormone secretion (SIADH)) are amongst the most challenging sequelae. The acute head trauma can lead (directly or indirectly) to dysfunction of the hypothalamic neurons secreting antidiuretic hormone (ADH) or of the posterior pituitary gland causing post-traumatic DI (PTDI). PTDI is usually diagnosed in the first days after the trauma presenting with hypotonic polyuria. Frequently, the poor general status of most patients prevents adequate fluid intake to compensate the losses and severe dehydration and hypernatremia occur. Management consists of careful monitoring of fluid balance and hormonal replacement. PTDI is associated with high mortality, particularly when presenting very early following the injury. In many surviving patients, the PTDI is transient, lasting a few days to a few weeks and in a minority of cases, it is permanent requiring management similar to that offered to patients with non-traumatic central DI. Full article

The release of airborne hazardous substances in the atmosphere has a direct effect on human health as, during the inhalation, an amount of concentration is inserted through the respiratory system into the human body, which can cause serious or even irreparable damage in health. One of the key problems in such cases is the prediction of the maximum individual exposure. Current state of the art methods, which are based on the concentration cumulative distribution function and require the knowledge of the concentration variance and the intermittency factor, have limitations. Recently, authors proposed a deterministic approach relating maximum individual exposure to parameters such as the fluctuation intensity and the concentration integral time scale. The purpose of the first part of this study is to validate the deterministic approach with the extensive dataset of the MUST (Mock Urban Setting Test) field experiment. This dataset includes 81 trials, which practically cover various atmospheric conditions and stability classes and contains in total 4004 non-zero concentration sensor data with time resolutions of 0.01–0.02 s. The results strengthen the usefulness of the deterministic model in predicting short-term maximum individual exposure. Another important output is the estimation of the methodology uncertainty involved. Full article

Whilst there is an increasing capability to instrument smart cities using fixed and mobile sensors to produce the big data to better understand and manage transportation use, there still exists a wide gap between the sustainability goals of smart cities, e.g., to promote less private car use at peak times, with respect to their ability to more dynamically support individualised shifts in multi-modal transportation use to help achieve such goals. We describe the development of the tripzoom system developed as part of the SUNSET—SUstainable social Network SErvices for Transport—project to research and develop a mobile and fixed traffic sensor system to help facilitate individual mobility shifts. Its main novelty was its ability to use mobile sensors to classify common multiple urban transportation modes, to generate information-rich individual and group mobility profiles and to couple this with the use of a targeted incentivised marketplace to gamify travel. This helps to promote mobility shifts towards achieving sustainability goals. This system was trialled in three European country cities operated as Living Labs over six months. Our main findings were that we were able to accomplish a level of behavioural shifts in travel behaviour. Hence, we have provided a proof-of-concept system that uses positive incentives to change individual travel behaviour. Full article

The ability to generate inducible pluripotent stem cells (iPSCs) and the potential for their use in treatment of human disease is of immense interest. Autoimmune diseases, with their limited treatment choices are a potential target for the clinical application of stem cell and iPSC technology. IPSCs provide three potential ways of treating autoimmune disease; (i) providing pure replacement of lost cells (immuno-reconstitution); (ii) through immune-modulation of the disease process in vivo; and (iii) for the purposes of disease modeling in vitro. In this review, we will use examples of systemic, system-specific and organ-specific autoimmunity to explore the potential applications of iPSCs for treatment of autoimmune diseases and review the evidence of iPSC technology in auto-immunity to date. Full article

In this paper, a dual band planar inverted F antenna (PIFA) has been investigated for cooperative on- and off-body communications. Free space and on-body performance parameters like return loss, bandwidth, radiation pattern and efficiency of this antenna are shown and investigated. The on- and off-body radio propagation channel performance at 2.45 GHz and 1.9 GHz have been investigated, respectively. Experimental investigations are performed both in the anechoic chamber and in an indoor environment. The path loss exponent has been extracted for both on- and off-body radio propagation scenarios. For on-body propagation, the path loss exponent is 2.48 and 2.22 in the anechoic chamber and indoor environment, respectively. The path loss exponent is 1.27 for off-body radio propagation situation. For on-body case, the path loss has been characterized for ten different locations on the body at 2.45 GHz, whereas for off-body case radio channel studies are performed for five different locations at 1.9 GHz. The proposed antenna shows a good on- and off-body radio channel performance. Full article

Pediatric endoscopy has evolved into an indispensable tool in the diagnosis and management of gastrointestinal diseases in children. However, there is limited literature focusing on quality improvement initiatives in pediatric endoscopy. The primary goal of this project was to reduce the no-show rate in the pediatric endoscopy unit. Also, we aimed to improve patient and family satisfaction with the procedure by identifying opportunities for improvement. A checklist was designed based on the potential causes of no-show. The endoscopy nurse coordinator reviewed the checklist when scheduling the procedure to identify patients at high risk for non-compliance. Once a risk factor was identified, appropriate actions were taken. She also made a pre-procedure phone call as a reminder and to address any of these risks for non-compliance if present. A patient satisfaction survey was used to identify potential areas for improvement. The no-show rate decreased from an average of 7% in the pre-intervention phase to 2% in the post-intervention phase (p = 0.009). 91% of the patients/family recorded an overall satisfaction of 4 or 5 on a scale of 1–5 5 being best). Quality improvement strategies decreased the no-show rate in the pediatric endoscopy unit. A patient satisfaction survey helped in identifying areas for improvement. Full article

The aim in this study was to assess the effectiveness of a quaternary ammonium chloride (QAC) surfactant in reducing surface staphylococcal contamination in a routinely operating medical ward occupied by patients who had tested positive for methicillin-resistant Staphylococcus aureus (MRSA). The QAC being tested is an antibacterial film that is sprayed onto a surface and can remain active for up to 8 h. A field experimental study was designed with the QAC plus daily hypochlorite cleaning as the experimental group and hypochlorite cleaning alone as the control group. The method of swabbing on moistened surfaces was used for sampling. It was found that 83% and 77% of the bedside surfaces of MRSA-positive and MRSA-negative patients respectively were contaminated with staphylococci at 08:00 hours, and that the staphylococcal concentrations increased by 80% at 1200 h over a 4-hour period with routine ward and clinical activities. Irrespective of the MRSA status of the patients, high-touch surfaces around the bed-units within the studied medical ward were heavily contaminated (ranged 1 to 276 cfu/cm² amongst the sites with positive culture) with staphylococcal bacteria including MRSA, despite the implementation of daily hypochlorite wiping. However, the contamination rate dropped significantly from 78% to 11% after the application of the QAC polymer. In the experimental group, the mean staphylococcal concentration of bedside surfaces was significantly (p < 0.0001) reduced from 4.4 ± 8.7 cfu/cm² at 08:00 hours to 0.07 ± 0.26 cfu/cm² at 12:00 hours by the QAC polymer. The results of this study support the view that, in addition to hypochlorite wiping, the tested QAC surfactant is a potential environmental decontamination strategy for preventing the transmission of clinically important pathogens in medical wards. Full article

The lack of appropriate human cardiomyocyte-based experimental platform has largely hindered the study of cardiac diseases and the development of therapeutic strategies. To date, somatic cells isolated from human subjects can be reprogramed into induced pluripotent stem cells (iPSCs) and subsequently differentiated into functional cardiomyocytes. This powerful reprogramming technology provides a novel in vitro human cell-based platform for the study of human hereditary cardiac disorders. The clinical potential of using iPSCs derived from patients with inherited cardiac disorders for therapeutic studies have been increasingly highlighted. In this review, the standard procedures for generating patient-specific iPSCs and the latest commonly used cardiac differentiation protocols will be outlined. Furthermore, the progress and limitations of current applications of iPSCs and iPSCs-derived cardiomyocytes in cell replacement therapy, disease modeling, drug-testing and toxicology studies will be discussed in detail. Full article

Novel drugs to treat tuberculosis are required and the identification of potential targets is important. Piperidinols have been identified as potential antimycobacterial agents (MIC < 5 μg/mL), which also inhibit mycobacterial arylamine N-acetyltransferase (NAT), an enzyme essential for mycobacterial survival inside macrophages. The NAT inhibition involves a prodrug-like mechanism in which activation leads to the formation of bioactive phenyl vinyl ketone (PVK). The PVK fragment selectively forms an adduct with the cysteine residue in the active site. Time dependent inhibition of the NAT enzyme from Mycobacterium marinum (M. marinum) demonstrates a covalent binding mechanism for all inhibitory piperidinol analogues. The structure activity relationship highlights the importance of halide substitution on the piperidinol benzene ring. The structures of the NAT enzymes from M. marinum and M. tuberculosis, although 74% identical, have different residues in their active site clefts and allow the effects of amino acid substitutions to be assessed in understanding inhibitory potency. In addition, we have used the piperidinol 3-dimensional shape and electrostatic properties to identify two additional distinct chemical scaffolds as inhibitors of NAT. While one of the scaffolds has anti-tubercular activity, both inhibit NAT but through a non-covalent mechanism. Full article

The benefit of calcium channel blockers for cardiovascular prevention against heart attack and stroke has not been firmly supported. We investigated the possible cardiovascular protective effect of diltiazem (DTZ) against injury induced by isoproterenol using a freely moving rat model in vivo. Sprague Dawley rats were injected subcutaneously (sc) with either 5 or 10 mg/kg of DTZ, or saline as control, twice daily for five doses. One hour after the last injection, a single dose of isoproterenol (30 mg/kg) was injected sc to each rat. Blood samples were collected serially for 6 h for measurement of adenine nucleotides (ATP, ADP and AMP) in red blood cell (RBC) by a validated HPLC. The study has shown isoproterenol induced 50% mortality and also increased RBC concentrations of AMP from 0.04 ± 0.02 to 0.29 ± 0.21 mM at the end of the experiment (p < 0.05). Treatment with 10 mg/kg of DTZ reduced mortality from 50% to <20% and attenuated the increase of RBC concentrations of AMP from +0.25 ± 0.22 in the control rats to +0.072 ± 0.092 mM (p < 0.05). The study concluded that 10 mg/kg of DTZ reduced mortality and breakdown of ATP induced by isoproterenol in rats. Full article

Many components of the cell, including lipids, proteins and both nuclear and mitochondrial DNA, are vulnerable to deleterious modifications caused by reactive oxygen species. If not repaired, oxidative DNA damage can lead to disease-causing mutations, such as in cancer. Base excision repair and nucleotide excision repair are the two DNA repair pathways believed to orchestrate the removal of oxidative lesions. However, recent findings suggest that the mismatch repair pathway may also be important for the response to oxidative DNA damage. This is particularly relevant in cancer where mismatch repair genes are frequently mutated or epigenetically silenced. In this review we explore how the regulation of oxidative DNA damage by mismatch repair proteins may impact on carcinogenesis. We discuss recent studies that identify potential new treatments for mismatch repair deficient tumours, which exploit this non-canonical role of mismatch repair using synthetic lethal targeting. Full article

The last decade has seen considerable advances in our understanding of the genetic basis of skin disease, as a consequence of high throughput sequencing technologies including next generation sequencing and whole exome sequencing. We have now determined the genes underlying several monogenic diseases, such as harlequin ichthyosis, Olmsted syndrome, and exfoliative ichthyosis, which have provided unique insights into the structure and function of the skin. In addition, through genome wide association studies we now have an understanding of how low penetrance variants contribute to inflammatory skin diseases such as psoriasis vulgaris and atopic dermatitis, and how they contribute to underlying pathophysiological disease processes. In this review we discuss strategies used to unravel the genes underlying both monogenic and complex trait skin diseases in the last 10 years and the implications on mechanistic studies, diagnostics, and therapeutics. Full article

Establishing effective toothbrushing routines using fluoridated toothpaste in infancy has been suggested as important to dental health throughout childhood and into adulthood. However, previous studies have revealed a number of potential barriers to, and facilitators of caregivers ability to establish early dyadic toothbrushing routines with pre-schoolers. However, as yet no qualitative research has been conducted to ascertain potential barriers and facilitators of the earliest dyadic toothbrushing in infancy, and nor has any previous research specifically focused on how novice mothers of first-born infants and preschoolers manage this task. This study therefore outlines findings from a qualitative interview study with first-time mothers of children aged 24–30 months (n = 16) exploring perceived barriers to and facilitators of early dyadic toothbrushing routines with infants and preschoolers. A number of key themes were identified from interview transcripts and an ‘ecological’ approach conceptualised maternally perceived barriers to and facilitators of dyadic toothbrushing. Proximal influences were found to be located within the caregiver-child relationship (‘micro-system’), including parental cognitions (e.g., PSE), parental behaviours (e.g., parenting practices) and infant and preschooler temperament and behaviours (e.g., tantrums). Distal factors were also identified as relevant to the establishment and maintenance of these routines, such as social support (‘exosystem’) and family history of tooth-brushing (‘chronosystem’). Full article

The advantage of microarray (array) over conventional karyotype for the diagnosis of fetal pathogenic chromosomal anomalies has prompted the use of microarrays in prenatal diagnostics. In this review we compare the performance of different array platforms (BAC, oligonucleotide CGH, SNP) and designs (targeted, whole genome, whole genome, and targeted, custom) and discuss their advantages and disadvantages in relation to prenatal testing. We also discuss the factors to consider when implementing a microarray testing service for the diagnosis of fetal chromosomal aberrations. Full article

Chronic inflammation and infection of the nasal sinuses, also referred to as Chronic Rhinosinusitis (CRS), severely affects patients’ quality of life. Adhesions, ostial stenosis, infection and inflammation relapses complicate chronic sinusitis treatment strategies. Drug-eluting stents, packings or implants have been suggested as reasonable alternatives for addressing these concerns. This article reviewed potential drug candidates for nasal implants, formulation methods/optimization and characterization methods. Clinical applications and important considerations were also addressed. Clinically-approved implants (Propel™ implant, the Relieva stratus™ MicroFlow spacer, and the Sinu-Foam™ spacer) for CRS treatment was an important focus. The advantages and limitations, as well as future considerations, challenges and the need for additional research in the field of nasal drug implant development, were discussed. Full article

In this paper, subject-specific narrowband (2.45 GHz) and ultra-wideband (3–10.6 GHz) on-body radio propagation studies in wireless body area networks (WBANs) were performed by characterizing the path loss for eight different human subjects of different shapes and sizes. The body shapes and sizes of the test subjects used in this study are characterised as thin, medium build, fatty, shorter, average height and taller. Experimental investigation was made in an indoor environment using a pair of printed monopoles (for the narrowband case) and a pair of tapered slot antennas (for the ultra-wideband (UWB) case). Results demonstrated that, due to the different sizes, heights and shapes of the test subjects, the path loss exponent value varies up to maximum of 0.85 for the narrowband on-body case, whereas a maximum variation of the path loss exponent value of 1.15 is noticed for the UWB case. In addition, the subject-specific behaviour of the on-body radio propagation channels was compared between narrowband and UWB systems, and it was deduced that the on-body radio channels are subject-specific for both narrowband and UWB system cases, when the same antennas (same characteristics) are used. The effect of the human body shape and size variations on the eight different on-body radio channels is also studied for both the narrowband and UWB cases. Full article

The purpose of this study was to examine the capability of hyperspectral narrow wavebands within the 400–900 nm range for distinguishing five cash crops commonly grown in Northeastern Ontario, Canada. Data were collected from ten different fields in the West Nipissing agricultural zone (46°24'N lat., 80°07'W long.) and included two of each of the following crop types; soybean (Glycine max), canola (Brassica napus L.), wheat (Triticum spp.), oat (Avena sativa), and barley (Hordeum vulgare). Stepwise discriminant analysis was used to assess the spectral separability of the various crop types under two scenarios; Scenario 1 involved testing separability of crops based on number of days after planting and Scenario 2 involved testing crop separability at specific dates across the growing season. The results indicate that select hyperspectral bands in the visual and near infrared (NIR) regions (400–900 nm) can be used to effectively distinguish the five crop species under investigation. These bands, which were used in a variety of combinations include B465, B485, B495, B515, B525, B535, B545, B625, B645, B665, B675, B695, B705, B715, B725, B735, B745, B755, B765, B815, B825, B885, and B895. In addition, although species classification could be achieved at any point during the growing season, the optimal time for satellite image acquisition was determined to be in late July or approximately 75–79 days after planting with the optimal wavebands located in the red-edge, green, and NIR regions of the spectrum. Full article

Chemotherapy is one of the major modalities in treating cancers. However, its effectiveness is limited by the acquisition of multidrug resistance (MDR). Several mechanisms could explain the up-regulation of MDR genes/proteins in cancer after chemotherapy. It is known that cancer stem cells (CSCs) play a role as master regulators. Therefore, understanding the mechanisms that regulate some traits of CSCs may help design efficient strategies to overcome chemoresistance. Different CSC phenotypes have been identified, including those found in some pediatric malignancies. As solid tumors in children significantly differ from those observed in adults, this review aims at providing an overview of the mechanistic relationship between MDR and CSCs in common solid tumors, and, in particular, focuses on clinical as well as experimental evidence of the relations between CSCs and MDR in neuroblastoma and hepatoblastoma. Finally, some novel approaches, such as concomitant targeting of multiple key transcription factors governing the stemness of CSCs, as well as nanoparticle-based approaches will also be briefly addressed. Full article

Using a generalized Doob’s h-transform we consider the zero-range process (ZRP) conditioned to carry an atypical current, with focus on the regime where the Gallavotti-Cohen symmetry loses its validity. For a single site we compute explicitly the boundary injection and absorption rates of an effective process which maps to a biased random walk. Our approach provides a direct probabilistic confirmation of the theory of “instantaneous condensation” which was proposed some while ago to explain the dynamical origin of the the failure of the Gallavotti-Cohen symmetry for high currents in the ZRP. However, it turns out that for stochastic dynamics with infinite state space care needs to be taken in the application of the Doob’s transform—we discuss in detail the sense in which the effective dynamics can be interpreted as “typical” for different regimes of the current phase diagram. Full article

Keratin 15 (K15) is type I keratin protein co-expressed with the K5/K14 pair present in the basal keratinocytes of all stratified epithelia. Although it is a minor component of the cytoskeleton with a variable expression pattern, nonetheless its expression has been reported as a stem cell marker in the bulge of hair follicles. Conversely, suprabasal expression of K15 has also been reported in both normal and diseased tissues, which is inconsistent with its role as a stem cell marker. Our recently published work has given evidence of the molecular pathways that seem to control the expression of K15 in undifferentiated and differentiated cells. In this article, we have critically reviewed the published work to establish the reliability of K15 as an epidermal stem cell marker. Full article

DNA methylation is a major epigenetic modification that is strongly involved in the physiological control of genome expression. DNA methylation patterns are largely modified in cancer cells and can therefore be used to distinguish cancer cells from normal tissues. This review describes the main technologies available for the detection and the discovery of aberrantly methylated DNA patterns. It also presents the different sources of biological samples suitable for DNA methylation studies. We discuss the interest and perspectives on the use of DNA methylation measurements for cancer diagnosis through examples of methylated genes commonly documented in the literature. The discussion leads to our consideration for why DNA methylation is not commonly used in clinical practice through an examination of the main requirements that constitute a reliable biomarker. Finally, we describe the main DNA methylation inhibitors currently used in clinical trials and those that exhibit promising results. Full article

Since their development over 60 years ago, antimicrobials have become an integral part of healthcare practice worldwide. Recently, this has been put in jeopardy by the emergence of widespread antimicrobial resistance, which is one of the major problems facing modern medicine. In the past, the development of new antimicrobials kept us one step ahead of the problem of resistance, but only three new classes of antimicrobials have reached the market in the last thirty years. A time is therefore approaching when we may not have effective treatment against bacterial infections, particularly for those that are caused by Gram-negative organisms. An important strategy to reduce the development of antimicrobial resistance is to use antimicrobials more appropriately, in ways that will prevent resistance. This involves a consideration of the pharmacokinetic and pharmacodynamics properties of antimicrobials, the possible use of combinations, and more appropriate choice of antimicrobials, which may include rapid diagnostic testing and antimicrobial cycling. Examples given in this review include Mycobacterium tuberculosis, Gram-negative and Gram-positive organisms. We shall summarise the current evidence for these strategies and outline areas for future development. Full article

The way in which Drosophila melanogaster acquires iron from the diet remains poorly understood despite iron absorption being of vital significance for larval growth. To describe the process of organismal iron absorption, consideration needs to be given to cellular iron import, storage, export and how intestinal epithelial cells sense and respond to iron availability. Here we review studies on the Divalent Metal Transporter-1 homolog Malvolio (iron import), the recent discovery that Multicopper Oxidase-1 has ferroxidase activity (iron export) and the role of ferritin in the process of iron acquisition (iron storage). We also describe what is known about iron regulation in insect cells. We then draw upon knowledge from mammalian iron homeostasis to identify candidate genes in flies. Questions arise from the lack of conservation in Drosophila for key mammalian players, such as ferroportin, hepcidin and all the components of the hemochromatosis-related pathway. Drosophila and other insects also lack erythropoiesis. Thus, systemic iron regulation is likely to be conveyed by different signaling pathways and tissue requirements. The significance of regulating intestinal iron uptake is inferred from reports linking Drosophila developmental, immune, heat-shock and behavioral responses to iron sequestration. Full article

MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a number of cancers. miRNAs have been found to participate in cell transformation and multiplication by acting as tumour oncogenes or suppressors; therefore, harnessing miRNAs may provide promising cancer therapeutics. Another major function of miRNAs is their activity as critical regulatory vehicles eliciting important regulatory processes in anti-tumour immunity through their influence on the development, differentiation and activation of various immune cells of both innate and adaptive immunity. This review aims to summarise recent findings focusing on the regulatory mechanisms of the development, differentiation, and proliferative aspects of the major immune populations by a diverse profile of miRNAs and may enrich our current understanding of the involvement of miRNAs in anti-tumour immunity. Full article

Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients. Full article

A honey bee queen mates with a number of drones a few days after she emerges as an adult. Spermatozoa of different drones are stored in her spermatheca and used for the rest of the queen’s life to fertilize eggs. Sperm usage is thought to be random, so that the patriline distribution within a honey bee colony would remain constant over time. In this study we assigned the progeny of a naturally mated honey bee queen to patrilines using microsatellite markers at the queen’s age of two, three and four years. No significant changes in patriline distribution occurred within each of two foraging seasons, with samples taken one and five months apart, respectively. Overall and pair-wise comparisons between the three analyzed years reached significant levels. Over the three-year period we found a trend for patrilines to become more equally represented with time. It is important to note that this study was performed with a single queen, and thus individual and population variation in sperm usage patterns must be assessed. We discuss long-term changes in patriline composition due to mixing processes in the queen’s spermatheca, following incomplete mixing of different drones’ sperm after mating. Full article

Biomechanical signals play an important role in normal disc metabolism and pathology. For instance, nucleus pulposus (NP) cells will regulate metabolic activities and maintain a balance between the anabolic and catabolic cascades. The former involves factors such as transforming growth factor-β (TGFβ) and mechanical stimuli, both of which are known to regulate matrix production through autocrine and paracrine mechanisms. The present study examined the combined effect of TGFβ and mechanical loading on anabolic activities in NP cells cultured in agarose constructs. Stimulation with TGFβ and dynamic compression reduced nitrite release and increased matrix synthesis and gene expression of aggrecan and collagen type II. The findings from this work has the potential for developing regenerative treatment strategies which could either slow down or stop the degenerative process and/or promote healing mechanisms in the intervertebral disc. Full article

Tetrodotoxin (TTX) is a powerful sodium channel blocker found in puffer fish and some marine animals. Cases of TTX poisoning most often result from puffer fish ingestion. Diagnosis is mainly from patient’s signs and symptoms or the detection of TTX in the leftover food. If leftover food is unavailable, the determination of TTX in the patient’s urine and/or plasma is essential to confirm the diagnosis. Although various methods for the determination of TTX have been published, most of them are for food tissue samples. Dealing with human urine and blood samples is much more challenging. Unlike in food, the amount of toxin in the urine and blood of a patient is generally extremely low; therefore a very sensitive method is required to detect it. In this regard, mass spectrometry (MS) methods are the best choice. Since TTX is a very polar compound, there will be lack of retention on conventional reverse-phase columns; use of ion pair reagent or hydrophilic interaction liquid chromatography (HILIC) can help solve this problem. The problem of ion suppression is another challenge in analyzing polar compound in biological samples. This review will discuss different MS methods and their pros and cons. Full article

Aqueous infusions of the leaves of the shrub Albertisia delagoensis (Menispermaceae) are used in South Africa in traditional Zulu medicine to alleviate a variety of symptoms, including fever, and intestinal problems. We report the analysis of such an aqueous extract using the HPLC-NMR technique. A number of polar compounds were identified, including proto-quercitol, nicotinic acid, allantoic acid, 3,4-dihydroxy-benzoic acid, phthalic acid and the aporphine alkaloid derivative roemrefidine. Allantoic acid and roemrefidine have been fully characterised by ¹H- and ¹³C-NMR and mass spectrometry. Earlier reports of antiplasmodial activity of roemrefidine and of A. delagoensis extracts are correlated with this study and with the antipyretic properties of neutral aqueous extracts. Full article

We investigated the relationship of stem diameter to tree, site and stand characteristics for six major tree species (trembling aspen, white birch, balsam fir, lodgepole pine, black spruce, and white spruce) in Alberta (Canada) with data from Alberta Sustainable Resource Development Permanent Sample Plots. Using non-linear mixed effects modeling techniques, we developed models to estimate diameter at breast height using height, crown and stand attributes. Mixed effects models (with plot as subject) using height, crown area, and basal area of the larger trees explained on average 95% of the variation in diameter at breast height across the six species with a root mean square error of 2.0 cm (13.4% of mean diameter). Fixed effects models (without plot as subject) including the Natural Sub-Region (NSR) information explained on average 90% of the variation in diameter at breast height across the six species with a root mean square error equal to 2.8 cm (17.9% of mean diameter). Selected climate variables provided similar results to models with NSR information. The inclusion of nutrient regime and moisture regime did not significantly improve the predictive ability of these models. Full article

The emergence of wireless technologies and advancements in on-body sensor design can enable change in the conventional health-care system, replacing it with wearable health-care systems, centred on the individual. Wearable monitoring systems can provide continuous physiological data, as well as better information regarding the general health of individuals. Thus, such vital-sign monitoring systems will reduce health-care costs by disease prevention and enhance the quality of life with disease management. In this paper, recent progress in non-invasive monitoring technologies for chronic disease management is reviewed. In particular, devices and techniques for monitoring blood pressure, blood glucose levels, cardiac activity and respiratory activity are discussed; in addition, on-body propagation issues for multiple sensors are presented. Full article

The convergence of distinct lineages upon interspecific hybridisation, including when accompanied by increases in ploidy (allopolyploidy), is a driving force in the origin of many plant species. In plant breeding too, both interspecific hybridisation and allopolyploidy are important because they facilitate introgression of alien DNA into breeding lines enabling the introduction of novel characters. Here we review how fluorescence in situ hybridisation (FISH) and genomic in situ hybridisation (GISH) have been applied to: 1) studies of interspecific hybridisation and polyploidy in nature, 2) analyses of phylogenetic relationships between species, 3) genetic mapping and 4) analysis of plant breeding materials. We also review how FISH is poised to take advantage of nextgeneration sequencing (NGS) technologies, helping the rapid characterisation of the repetitive fractions of a genome in natural populations and agricultural plants. Full article

The two main histological esophageal cancer types, adenocarcinoma and squamous cell carcinoma, differ in incidence, geographic distribution, ethnic pattern and etiology. This article focuses on epidemiology with particular reference to geographic and temporal variations in incidence, along with a review of the evidence supporting environmental and genetic factors involved in esophageal carcinogenesis. Squamous cell carcinoma of the esophagus remains predominantly a disease of the developing world. In contrast, esophageal adenocarcinoma is mainly a disease of western developed societies, associated with obesity and gastro-esophageal reflux disease. There has been a dramatic increase in the incidence of adenocarcinoma in developed countries in parallel with migration of both esophageal and gastric adenocarcinomas towards the gastro-esophageal junction. Full article

The effect of the ethanolic extract of Elaeagnus angustifolia was tested on dispersed smooth muscle cells (SMC) of the guinea pigs. A slight contractile response was observed when SMC were treated with low concentrations of the extract. Pre-treatment of the SMC with ethanolic extract of E. angustifolia caused concentration dependent inhibition of acetylcholine-induced contractions of the SMC. Full article