Inner experience of pain: imagination of pain while viewing images showing painful events forms subjective pain representation in human brain.
Pain is an unpleasant sensation, and at the same time, it is always subjective and affective. Ten healthy subjects viewed 3 counterbalanced blocks of images from the International Affective Picture System: images showing painful events and those evoking emotions of fear and rest. They were instructed to imagine pain in their own body while viewing each image showing a painful event (the imagination of pain). Using functional magnetic resonance imaging, we compared cerebral hemodynamic responses during the imagination of pain with those to emotions of fear and rest. The results show that the imagination of pain is associated with increased activity in several brain regions involved in the pain-related neural network, notably the anterior cingulate cortex (ACC), right anterior insula, cerebellum, posterior parietal cortex, and secondary somatosensory cortex region, whereas increased activity in the ACC and amygdala is associated with the viewing of images evoking fear. Our results indicate that the imagination of pain even without physical injury engages the cortical representations of the pain-related neural network more specifically than emotions of fear and rest; it also engages the common representation (i.e., in ACC) between the imagination of pain and the emotion of fear.


Prediction of adverse perinatal outcome of small-for-gestational-age pregnancy using size centiles and conditional growth centiles.
To test whether adding conditional growth centiles to size centiles of estimated fetal weight (EFW) improves prediction of adverse perinatal outcome in pregnancies with or at risk of having a small-for-gestational-age (SGA) fetus. This prospective longitudinal study included pregnant women at risk of or diagnosed with an SGA (≤ 5(th) centile) fetus. They underwent serial ultrasound measurements and the final two were included in the analyses for this study. The EFW was categorized into normal (> 5(th) or 10(th) centile) and abnormal (≤ 5(th) or 10(th) centile) for size and conditional growth before entering the variables into log-binomial regression analyses. Adverse outcomes were delivery < 37 weeks, operative delivery due to fetal distress, 5-min Apgar score < 7, newborn hypoglycemia (glucose < 2.0 mmol/L), admission to the neonatal intensive care unit and perinatal mortality. A combined outcome variable ('any adverse outcome') included one or more adverse outcomes. Complete biometric data were obtained for 211 women. Conditional growth and size centiles contributed independently to the prediction of adverse outcome. Combining conditional growth and size centiles significantly improved the prediction of outcomes compared with size centiles alone (e.g. for 5(th) centile cut-off for any adverse outcome, P = 0.023, log-likelihood test). Using a 5(th) centile threshold, for any adverse outcome, the specificity of 78% (95% CI, 70-84%) using size centile as a predictor was improved to 94% (95% CI, 89-97%) when conditional growth centile was added to the model, whereas the sensitivity was not significantly changed (60% (95% CI, 49-69%) vs 39% (95% CI, 30-50%)). Size centiles and conditional growth centiles contribute independently to the prediction of adverse perinatal outcome, and their combination further improves the prediction model. The results support an increased use of conditional growth centiles in the monitoring of fetuses at risk. Copyright © 2015 ISUOG. Published by John Wiley & Sons Ltd.


Dissipative out-of-equilibrium assembly of man-made supramolecular materials.
The use of dissipative self-assembly driven by chemical reaction networks for the creation of unique structures is gaining in popularity. In dissipative self-assembly, precursors are converted into self-assembling building blocks by the conversion of a source of energy, typically a photon or a fuel molecule. The self-assembling building block is intrinsically unstable and spontaneously reverts to its original precursor, thus giving the building block a limited lifetime. As a result, its presence is kinetically controlled, which gives the associated supramolecular material unique properties. For instance, formation and properties of these materials can be controlled over space and time by the kinetics of the coupled reaction network, they are autonomously self-healing and they are highly adaptive to small changes in their environment. By means of an example of a biological dissipative self-assembled material, the unique concepts at the basis of these supramolecular materials will be discussed. We then review recent efforts towards man-made dissipative assembly of structures and how their unique material properties have been characterized. In order to help further the field, we close with loosely defined design rules that are at the basis of the discussed examples.


Effect of interfacial reaction rate on the morphogenesis of nanostructured coatings in a simulated electrodeposition process.
Brownian dynamics simulations (BDSs) are performed to investigate the influence of interfacial electrochemical reaction rate on the evolution of coating morphology on circular fibres. The boundary condition for the fluid phase concentration, representing the balance between the rates of interfacial reaction and transport of ions by bulk diffusion, is incorporated into the BDS by using a reaction probability, P(s). Different modes of growth, ranging from diffusion limited ([Formula: see text]) to reaction controlled [Formula: see text], are studied. It is found that, consistent with experimental observations, two distinct morphological regimes exist, with a dense and uniform structure for [Formula: see text] (reaction limited deposition (RLD)) and an open and porous one as [Formula: see text] (diffusion limited deposition (DLD)). An analysis of the fractal dimension indicates that this morphological transition occurs at P(s)≈0.3. Long-time power-law scalings for the evolution of thickness [Formula: see text] and roughness (ξ) of the coating exist, i.e. [Formula: see text] with 0.86≤α≤0.91 and 0.56≤β≤0.93 for 0.01≤P(s)≤1. These values are different from those reported for sequential, pseudo-time lattice simulations on planar surfaces, signifying the importance of multiparticle dynamics and surface curvature. The internal structure and porosity of the coating are characterized quantitatively by the radial density profile, pair correlation function, two-point probability function, void distribution function and pore area distribution. For RLD the radial density, ρ(n), remains nearly constant, while for DLD ρ(n) follows a power law, [Formula: see text]. The coating exhibits short ranged order in the RLD regime while a long range order is created by DLD. The void distribution function becomes broader with increasing P(s), indicating that in the RLD regime the coating consists of small and spherical pores, while in the DLD regime large and elongated pores are obtained. The pore area distribution shows narrower distributions in DLD for small pores, while the area of the largest pore increases by nearly three orders of magnitude as one moves from the RLD to the DLD regime. Such morphological diversity could be potentially exploited for applications such as percolation, catalysis and surface protection.


Population-level plasticity in foraging behavior of western gulls (Larus occidentalis).
Plasticity in foraging behavior among individuals, or across populations may reduce competition. As a generalist carnivore, western gulls (Larus occidentalis) consume a wide range of marine and terrestrial foods. However, the foraging patterns and habitat selection (ocean or land) of western gulls is not well understood, despite their ubiquity in coastal California. Here, we used GPS loggers to compare the foraging behavior and habitat use of western gulls breeding at two island colonies in central California. Gulls from offshore Southeast Farallon Island (SFI; n = 41 gulls) conducted more oceanic trips (n = 90) of shorter duration (3.8 ± 3.3 SD hours) and distance (27.1 ± 20.3 km) than trips to the mainland (n = 41) which were nearly 4 times longer and 2 times farther away. In contrast, gulls from coastal Año Nuevo Island (ANI; n = 20 gulls) foraged at sites on land more frequently (n = 103) but trip durations (3.6 ± 2.4 h) and distances (20.8 ± 9.4 km) did not differ significantly from oceanic trips (n = 42) where trip durations were only slightly shorter (2.9 ± 2.7 h) and equidistant (20.6 ± 12.1 km). Gulls from both colonies visited more sites while foraging at sea but spent significantly longer (3-5 times) durations at each site visited on land. Foraging at sea was also more random compared to foraging trips over land where gulls from both colonies visited the same sites on multiple trips. The total home range of gulls from SFI (14,230 km2) was 4.5 times larger than that of gulls from ANI, consistent with greater resource competition resulting from a larger abundance of seabirds at SFI. Population-level plasticity in foraging behavior was evident and dependent on habitat type. In addition, gulls from SFI were away foraging longer than gulls from ANI (22% vs. 7.5%, respectively), which impacts the defense of territories and attempts at nest predation by conspecifics. Our results can be used to explain lower chick productivity at SFI, and can provide insight into increased gull activity in urban areas.


Intermittent catheterisation for long-term bladder management.
Intermittent catheterisation is a commonly recommended procedure for people with incomplete bladder emptying. There are now several designs of intermittent catheter (e.g. different lengths, 'ready to use' presentation) with different materials (e.g. PVC-free) and coatings (e.g. hydrophilic). The most frequent complication of intermittent catheterisation is urinary tract infection (UTI), but satisfaction, preference and ease of use are also important to users. It is unclear which catheter designs, techniques or strategies affect the incidence of UTI, which are preferable to users and which are most cost effective. To compare one type of catheter design versus another, one type of catheter material versus another, aseptic catheterisation technique versus clean technique, single-use (sterile) catheters versus multiple-use (clean) catheters, self-catheterisation versus catheterisation by others and any other strategies designed to reduce UTI and other complications or improve user-reported outcomes (user satisfaction, preference, ease of use) and cost effectiveness in adults and children using intermittent catheterisation for incomplete bladder emptying. We searched the Cochrane Incontinence Group Specialised Register, which contains trials identified from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE in process, and handsearching of journals and conference proceedings (searched 30 September 2013), the reference lists of relevant articles and conference proceedings, and we attempted to contact other investigators for unpublished data or for clarification. Randomised controlled trials (RCTs) or randomised cross-over trials comparing at least two different catheter designs, catheterisation techniques or strategies. Two review authors assessed the methodological quality of trials and abstracted data. For dichotomous variables, risk ratios and 95% confidence intervals were derived for each outcome where possible. For continuous variables, mean differences and 95% confidence intervals were calculated for each outcome. Because of trial heterogeneity, it was not always possible to combine data to give an overall estimate of treatment effect. Thirty-one trials met the inclusion criteria, including 13 RCTs and 18 cross-over trials. Most were small (less than 60 participants completed), although five trials had more than 100 participants. There was considerable variation in length of follow-up and definitions of UTI. Participant dropout was a problem for several trials, particularly where there was long-term follow-up to measure incidence of UTI. Fifteen trials were more than 10 years old and focused mainly on comparing different catheterisation techniques (e.g. single versus multiple-use) on clinical outcomes whereas, several more recent trials have focused on comparing different types of catheter designs or materials, especially coatings, and user preference. It was not possible to combine data from some trials owing to variations in the catheters tested and in particular the catheter coatings. Where there were data, confidence intervals around estimates were wide and hence clinically important differences in UTI and other outcomes could neither be identified nor reliably ruled out. No study assessed cost-effectiveness. Despite a total of 31 trials, there is still no convincing evidence that the incidence of UTI is affected by use of aseptic or clean technique, coated or uncoated catheters, single (sterile) or multiple-use (clean) catheters, self-catheterisation or catheterisation by others, or by any other strategy. Results from user-reported outcomes varied. The current research evidence is weak and design issues are significant. More well-designed trials are strongly recommended. Such trials should include analysis of cost-effectiveness because there are likely to be substantial differences associated with the use of different catheter designs, catheterisation techniques and strategies.


Migratory movements of pygmy blue whales (Balaenoptera musculus brevicauda) between Australia and Indonesia as revealed by satellite telemetry.
In Australian waters during the austral summer, pygmy blue whales (Balaenoptera musculus brevicauda) occur predictably in two distinct feeding areas off western and southern Australia. As with other blue whale subspecies, outside the austral summer their distribution and movements are poorly understood. In order to describe the migratory movements of these whales, we present the satellite telemetry derived movements of eleven individuals tagged off western Australia over two years. Whales were tracked from between 8 and 308 days covering an average distance of 3,009±892 km (mean ± se; range: 832 km-14,101 km) at a rate of 21.94±0.74 km per day (0.09 km-455.80 km/day). Whales were tagged during March and April and ultimately migrated northwards post tag deployment with the exception of a single animal which remained in the vicinity of the Perth Canyon/Naturaliste Plateau for its eight day tracking period. The tagged whales travelled relatively near to the Australian coastline (100.0±1.7 km) until reaching a prominent peninsula in the north-west of the state of Western Australia (North West Cape) after which they travelled offshore (238.0±13.9 km). Whales reached the northern terminus of their migration and potential breeding grounds in Indonesian waters by June. One satellite tag relayed intermittent information to describe aspects of the southern migration from Indonesia with the animal departing around September to arrive in the subtropical frontal zone, south of western Australia in December. Throughout their migratory range, these whales are exposed to impacts associated with industry, fishing and vessel traffic. These movements therefore provide a valuable tool to industry when assessing potential interactions with pygmy blue whales and should be considered by conservation managers and regulators when mitigating impacts of development. This is particularly relevant for this species as it continues to recover from past exploitation.


Removal and fate of micropollutants in a sponge-based moving bed bioreactor.
This study investigated the removal of micropollutants using polyurethane sponge as attached-growth carrier. Batch experiments demonstrated that micropollutants could adsorb to non-acclimatized sponge cubes to varying extents. Acclimatized sponge showed significantly enhanced removal of some less hydrophobic compounds (log D<2.5), such as ibuprofen, acetaminophen, naproxen, and estriol, as compared with non-acclimatized sponge. The results for bench-scale sponge-based moving bed bioreactor (MBBR) system elucidated compound-specific variation in removal, ranging from 25.9% (carbamazepine) to 96.8% (β-Estradiol 17-acetate) on average. In the MBBR system, biodegradation served as a major removal pathway for most compounds. However, sorption to sludge phase was also a notable removal mechanism of some persistent micropollutants. Particularly, carbamazepine, ketoprofen and pentachlorophenol were found at high concentrations (7.87, 6.05 and 5.55 μg/g, respectively) on suspended biosolids. As a whole, the effectiveness of MBBR for micropollutant removal was comparable with those of activated sludge processes and MBRs.


Aspirin in Alzheimer's disease: increased risk of intracerebral hemorrhage: cause for concern?
In a randomized controlled trial in Alzheimer's disease (AD), we found a higher number of intracerebral hemorrhages (ICHs) in patients randomized to aspirin treatment. Here, we evaluate the literature on the risk of ICH as a complication in patients with AD treated with aspirin. Systematic review and comparison of the occurrence of events over time between the aspirin and control group in each trial using Cox regression analysis. Estimated hazard ratios (HRs) were combined in a pooled HR. Two randomized controlled trials on aspirin for AD were found. In the Evaluation of Vascular Care in Alzheimer's Disease (EVA) trial (conducted in our center), 4.6% of patients in the group receiving a multicomponent treatment that included aspirin had an ICH (3/65; 95% confidence interval [CI], 1.0 to 12.9) versus 0% in the control group (0/58; 95% CI, 0 to 6.2). In the Aspirin in Alzheimer's Disease (AD2000) trial, these proportions were, respectively, 2.6% (4/156; 95% CI, 0.7 to 6.4) and 0% (0/154; 95% CI, 0 to 2.4). The pooled proportion of ICHs in the aspirin group is 3.2% (7/221; 95% CI, 1.3 to 6.4) versus 0% in the control group (0/212; 95% CI, 0 to 1.7). The pooled HR for an ICH in AD patients using aspirin is 7.63 (95% CI, 0.72 to 81.00; P=0.09). Although the number of cases in both trials is small, our findings suggest that aspirin use in AD might pose an increased risk of ICH, whereas it has no effect on cognition. If there is an unequivocal cardiovascular indication for aspirin, it should not be withheld in AD patients.


Toxicity of dopamine to striatal neurons in vitro and potentiation of cell death by a mitochondrial inhibitor.
Intrastriatal injections of the mitochondrial toxins malonate and 3-nitropropionic acid produce selective cell death similar to that seen in transient ischemia and Huntington's disease. The extent of cell death can be attenuated by pharmacological or surgical blockade of cortical glutamatergic input. It is not known, however, if dopamine contributes to toxicity caused by inhibition of mitochondrial function. Exposure of primary striatal cultures to dopamine resulted in dose-dependent death of neurons. Addition of medium supplement containing free radical scavengers and antioxidants decreased neuronal loss. At high concentrations of the amine, cell death was predominantly apoptotic. Methyl malonate was used to inhibit activity of the mitochondrial respiratory chain. Neither methyl malonate (50 microM) nor dopamine (2.5 microM) caused significant toxicity when added individually to cultures, whereas simultaneous addition of both compounds killed 60% of neurons. Addition of antioxidants and free radical scavengers to the incubation medium prevented this cell death. Dopamine (up to 250 microM) did not alter the ATP/ADP ratio after a 6-h incubation. Methyl malonate, at 500 microM, reduced the ATP/ADP ratio by approximately 30% after 6 h; this decrease was not augmented by coincubation with 25 microM dopamine. Our results suggest that dopamine causes primarily apoptotic death of striatal neurons in culture without damaging cells by an early adverse action on oxidative phosphorylation. However, when combined with minimal inhibition of mitochondrial function, dopamine neurotoxicity is markedly enhanced.


Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia.
Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.


Radiolysis generates a complex organosynthetic chemical network.
The architectural features of cellular life and its ecologies at larger scales are built upon foundational networks of reactions between molecules that avoid a collapse to equilibrium. The search for life's origins is, in some respects, a search for biotic network attributes in abiotic chemical systems. Radiation chemistry has long been employed to model prebiotic reaction networks, and here we report network-level analyses carried out on a compiled database of radiolysis reactions, acquired by the scientific community over decades of research. The resulting network shows robust connections between abundant geochemical reservoirs and the production of carboxylic acids, amino acids, and ribonucleotide precursors-the chemistry of which is predominantly dependent on radicals. Moreover, the network exhibits the following measurable attributes associated with biological systems: (1) the species connectivity histogram exhibits a heterogeneous (heavy-tailed) distribution, (2) overlapping families of closed-loop cycles, and (3) a hierarchical arrangement of chemical species with a bottom-heavy energy-size spectrum. The latter attribute is implicated with stability and entropy production in complex systems, notably in ecology where it is known as a trophic pyramid. Radiolysis is implicated as a driver of abiotic chemical organization and could provide insights about the complex and perhaps radical-dependent mechanisms associated with life's origins.


Smoking and intention to quit in deprived areas of Glasgow: is it related to housing improvements and neighbourhood regeneration because of improved mental health?
People living in areas of multiple deprivation are more likely to smoke and less likely to quit smoking. This study examines the effect on smoking and intention to quit smoking for those who have experienced housing improvements (HI) in deprived areas of Glasgow, UK, and investigates whether such effects can be explained by improved mental health. Quasi-experimental, 2-year longitudinal study, comparing residents' smoking and intention to quit smoking for HI group (n=545) with non-HI group (n=517), adjusting for baseline (2006) sociodemographic factors and smoking status. SF-12 mental health scores were used to assess mental health, along with self-reported experience of, and General Practitioner (GP) consultations for, anxiety and depression in the last 12 months. There was no relationship between smoking and HI, adjusting for baseline rates (OR=0.97, 95% CI 0.57 to 1.67, p=0.918). We found an association between intention to quit and HI, which remained significant after adjusting for sociodemographics and previous intention to quit (OR 2.16, 95% CI 1.12 to 4.16, p=0.022). We found no consistent evidence that this association was attenuated by improvement in our three mental health measures. Providing residents in disadvantaged areas with better housing may prompt them to consider quitting smoking. However, few people actually quit, indicating that residential improvements or changes to the physical environment may not be sufficient drivers of personal behavioural change. It would make sense to link health services to housing regeneration projects to support changes in health behaviours at a time when environmental change appears to make behavioural change more likely.


One-week cocoa flavanol intake increases prefrontal cortex oxygenation at rest and during moderate-intensity exercise in normoxia and hypoxia.
During exercise in hypoxia, O2 delivery to brain and muscle is compromised, and oxidative stress is elicited. Cocoa flavanols (CF) have antioxidant capacities and can increase blood flow by stimulating endothelial function. We aimed to examine the effects of 7-day CF intake on oxidative stress, nitric oxide production, and tissue oxygenation in response to exercise in normobaric hypoxia (14.3% O2). In a randomized, double-blind, cross-over study, 14 well-trained male cyclists completed four trials: exercise in normoxia or hypoxia, after 7-day CF or placebo intake. Flow-mediated dilation (FMD) was measured before intake of the last dose CF or placebo. One hundred minutes later, 20-min steady-state (SS; 45% V̇o2max) and 20-min time trial (TT) (cycling) were performed. Blood samples were taken. Prefrontal and muscular oxygenation was assessed by near-infrared spectroscopy. At baseline, FMD was increased by CF. Hypoxia increased exercise-induced elevations in lipid peroxidation and antioxidant capacity. CF suppressed exercise-induced lipid peroxidation but did not influence antioxidant capacity. At rest and during SS, prefrontal and muscular oxygenation was decreased by hypoxia. CF elevated prefrontal oxygenation but did not impact muscular oxygenation. During TT, hypoxia accelerated the exercise-induced decrease in prefrontal oxygenation, but not in muscular oxygenation. During TT, CF did not alter prefrontal and muscular oxygenation. CF did not change plasma nitrite, nitrate, and arginine:citrulline. During high-intensity exercise, CF improved neither tissue oxygenation nor performance in well-trained athletes. At rest and during moderate-intensity exercise, CF reduced exercise-induced lipid peroxidation and partially restored the hypoxia-induced decline in prefrontal oxygenation. NEW & NOTEWORTHY For the first time, we showed that CF had beneficial effects on endothelial function at rest, as well as on prefrontal oxygenation at rest and during moderate-intensity exercise, both in normoxia and hypoxia. Moreover, we showed that CF intake inhibited oxidative stress during exhaustive exercise in hypoxia.


Factors Associated With HIV Testing in Youth in the United States: An Integrative Review.
We used an integrative review to synthesize existing literature on the factors associated with HIV testing by youth ages 13 to 24 years in the United States. PubMed, CINAHL, PsycINFO, and Google Scholar were systematically searched and 44 original research studies met our criteria. A directed qualitative content analysis was conducted to integrate findings according to the personal, relationship, community, and society levels of the social-ecological model. Female gender, African American race, age, and physical illness were some of the factors more consistently associated with HIV testing. Modifiable factors such as fear, drug use, poor condom use, partner communication, and multiple sexual partners were also noted as influencing HIV testing in youth. Our integrative review revealed gaps in the literature that need further exploration, particularly in the area of community and society influences on HIV testing for youth. Implications for research, practice, and policy are discussed.


Loss of 10p material in a child with human papillomavirus-positive disseminated bilateral retinoblastoma.
Retinoblastoma (RB) is a malignant childhood tumor that results from loss or inactivation of both alleles of the RB1 gene. Human papillomavirus (HPV) DNA sequences have been found in RB tissue, suggesting a role of the viral infection with RB. We here describe a child with disseminated bilateral RB without familial history, who displayed a loss of material from 10p. Fluorescence in situ hybridization studies showed a somatic loss of both alleles of the RB1 gene. Moreover, sequences for HPV-6a were detected on DNA extracted from eye tumor tissue and from nonstimulated peripheral blood leukocyte cultures. The eye tumor tissue was also positive for HPV L1 viral proteins. Repeated loss of the short arm of chromosome 10 in HPV-transfected keratinocytes has been reported. Loss of heterozygosity in 10p14 approximately p15 is also frequent in cervical cancers. Therefore, it seems probable that the abnormalities on 10p detected in the present case are related to the HPV infection. Thus, HPV could be a cofactor in the progression of RB by promoting nonrandom additional mutations.


Cervical and scapulothoracic stabilization exercises with and without connective tissue massage for chronic mechanical neck pain: A prospective, randomised controlled trial.
This study was planned to assess and compare the effectiveness of cervical and scapulothoracic stabilization exercise treatment with and without connective tissue massage (CTM) on pain, anxiety, and the quality of life in patients with chronic mechanical neck pain (MNP). Sixty patients with chronic MNP (18-65 years) were recruited and randomly allocated into stabilization exercise with (Group 1, n = 30) and without the CTM (Group 2, n = 30). The program was carried out for 12 sessions, 3 days/week in 4 weeks. Pain intensity with Visual Analog Scale, pressure pain threshold with digital algometer (JTech Medical Industries, ZEVEX Company), level of anxiety with Spielberger State Trait Anxiety Inventory, and quality of life with Short Form-36 were evaluated before and after the treatment. After the program, pain intensity and the level of anxiety decrease, physical health increase in Group 1 and 2 were found (p < 0.05). Pressure pain threshold and mental health increase were detected in only Group 1 (p < 0.05). The intergroup comparison showed that significant difference in pain intensity at night, pressure pain threshold, state anxiety and mental health were seen in favor of Group 1 (p < 0.05). The study suggested that stabilization exercises with and without the CTM might be a useful treatment for patients with chronic MNP. However, stabilization exercises with CTM might be superior in improving pain intensity at night, pressure pain threshold, state anxiety and mental health compared to stabilization exercise alone.


Subwavelength vortical plasmonic lattice solitons.
We present a theoretical study of vortical plasmonic lattice solitons, which form in two-dimensional arrays of metallic nanowires embedded into nonlinear media with both focusing and defocusing Kerr nonlinearities. Their existence, stability, and subwavelength spatial confinement are investigated in detail.


Strength training for plantar fasciitis and the intrinsic foot musculature: A systematic review.
The aim was to critically evaluate the literature investigating strength training interventions in the treatment of plantar fasciitis and improving intrinsic foot musculature strength. A search of PubMed, CINHAL, Web of Science, SPORTSDiscus, EBSCO Academic Search Complete and PEDRO using the search terms plantar fasciitis, strength, strengthening, resistance training, intrinsic flexor foot, resistance training. Seven articles met the eligibility criteria. Methodological quality was assessed using the modified Downs and Black checklist. All articles showed moderate to high quality, however external validity was low. A comparison of the interventions highlights significant differences in strength training approaches to treating plantar fasciitis and improving intrinsic strength. It was not possible to identify the extent to which strengthening interventions for intrinsic musculature may benefit symptomatic or at risk populations to plantar fasciitis. There is limited external validity that foot exercises, toe flexion against resistance and minimalist running shoes may contribute to improved intrinsic foot musculature function. Despite no plantar fascia thickness changes being observed through high-load plantar fascia resistance training there are indications that it may aid in a reduction of pain and improvements in function. Further research should use standardised outcome measures to assess intrinsic foot musculature strength and plantar fasciitis symptoms.


Deep Aging Clocks: The Emergence of AI-Based Biomarkers of Aging and Longevity.
First published in 2016, predictors of chronological and biological age developed using deep learning (DL) are rapidly gaining popularity in the aging research community. These deep aging clocks can be used in a broad range of applications in the pharmaceutical industry, spanning target identification, drug discovery, data economics, and synthetic patient data generation. We provide here a brief overview of recent advances in this important subset, or perhaps superset, of aging clocks that have been developed using artificial intelligence (AI).


Functional cartography of complex metabolic networks.
High-throughput techniques are leading to an explosive growth in the size of biological databases and creating the opportunity to revolutionize our understanding of life and disease. Interpretation of these data remains, however, a major scientific challenge. Here, we propose a methodology that enables us to extract and display information contained in complex networks. Specifically, we demonstrate that we can find functional modules in complex networks, and classify nodes into universal roles according to their pattern of intra- and inter-module connections. The method thus yields a 'cartographic representation' of complex networks. Metabolic networks are among the most challenging biological networks and, arguably, the ones with most potential for immediate applicability. We use our method to analyse the metabolic networks of twelve organisms from three different superkingdoms. We find that, typically, 80% of the nodes are only connected to other nodes within their respective modules, and that nodes with different roles are affected by different evolutionary constraints and pressures. Remarkably, we find that metabolites that participate in only a few reactions but that connect different modules are more conserved than hubs whose links are mostly within a single module.


The mechanism of abrupt transition between theta and hyper-excitable spiking activity in medial entorhinal cortex layer II stellate cells.
Recent studies have shown that stellate cells (SCs) of the medial entorhinal cortex become hyper-excitable in animal models of temporal lobe epilepsy. These studies have also demonstrated the existence of recurrent connections among SCs, reduced levels of recurrent inhibition in epileptic networks as compared to control ones, and comparable levels of recurrent excitation among SCs in both network types. In this work, we investigate the biophysical and dynamic mechanism of generation of the fast time scale corresponding to hyper-excitable firing and the transition between theta and fast firing frequency activity in SCs. We show that recurrently connected minimal networks of SCs exhibit abrupt, threshold-like transition between theta and hyper-excitable firing frequencies as the result of small changes in the maximal synaptic (AMPAergic) conductance. The threshold required for this transition is modulated by synaptic inhibition. Similar abrupt transition between firing frequency regimes can be observed in single, self-coupled SCs, which represent a network of recurrently coupled neurons synchronized in phase, but not in synaptically isolated SCs as the result of changes in the levels of the tonic drive. Using dynamical systems tools (phase-space analysis), we explain the dynamic mechanism underlying the genesis of the fast time scale and the abrupt transition between firing frequency regimes, their dependence on the intrinsic SC's currents and synaptic excitation. This abrupt transition is mechanistically different from others observed in similar networks with different cell types. Most notably, there is no bistability involved. 'In vitro' experiments using single SCs self-coupled with dynamic clamp show the abrupt transition between firing frequency regimes, and demonstrate that our theoretical predictions are not an artifact of the model. In addition, these experiments show that high-frequency firing is burst-like with a duration modulated by an M-current.


A viral member of the ERV1/ALR protein family participates in a cytoplasmic pathway of disulfide bond formation.
Proteins of the ERV1/ALR family are encoded by all eukaryotes and cytoplasmic DNA viruses for which substantial sequence information is available. Nevertheless, the roles of these proteins are imprecisely known. Multiple alignments of ERV1/ALR proteins indicated an invariant C-X-X-C motif, but no similarity to the thioredoxin fold was revealed by secondary structure predictions. We chose a virus model to investigate the role of these proteins as thiol oxidoreductases. When cells were infected with a mutant vaccinia virus in which the E10R gene encoding an ERV1/ALR family protein was repressed, the disulfide bonds of three other viral proteins-namely, the L1R and F9L proteins and the G4L glutaredoxin-were completely reduced. The same outcome occurred when Cys-43 or Cys-46, the putative redox cysteines of the E10R protein, was mutated to serine. These two cysteines were disulfide bonded during a normal virus infection but not if the synthesis of other viral late proteins was inhibited or the E10R protein was expressed by itself in uninfected cells, suggesting a requirement for an upstream viral thiol oxidoreductase. Remarkably, the cysteine-containing domains of the E10R and L1R viral membrane proteins and the glutaredoxin are in the cytoplasm, in which assembly of vaccinia virions occurs, rather than in the oxidizing environment of the endoplasmic reticulum. These data indicated a viral pathway of disulfide bond formation in which the E10R protein has a central role. By extension, the ERV1/ALR family may represent a ubiquitous class of cellular thiol oxidoreductases that interact with glutaredoxins or thioredoxins.


The impact of a radiologist-led workshop on MRI target volume delineation for radiotherapy.
Magnetic resonance imaging (MRI) is increasingly used for target volume delineation in radiotherapy due to its superior soft tissue visualisation compared to computed tomography (CT). The aim of this study was to assess the impact of a radiologist-led workshop on inter-observer variability in volume delineation on MRI. Data from three separate studies evaluating the impact of MRI in lung, breast and cervix were collated. At pre-workshop evaluation, observers involved in each clinical site were instructed to delineate specified volumes. Radiologists specialising in each cancer site conducted an interactive workshop on interpretation of images and anatomy for each clinical site. At post-workshop evaluation, observers repeated delineation a minimum of 2 weeks after the workshops. Inter-observer variability was evaluated using dice similarity coefficient (DSC) and volume similarity (VOLSIM) index comparing reference and observer volumes. Post-workshop primary gross tumour volumes (GTV) were smaller than pre-workshop volumes for lung with a mean percentage reduction of 10.4%. Breast clinical target volumes (CTV) were similar but seroma volumes were smaller post-workshop on both supine (65% reduction) and prone MRI (73% reduction). Based on DSC scores, improvement in inter-observer variability was seen for the seroma cavity volume on prone MRI with a reduction in DSC score range from 0.4-0.8 to 0.7-0.9. Breast CTV demonstrated good inter-observer variability scores (mean DSC 0.9) for both pre- and post-workshop. Post-workshop observer delineated cervix GTV was smaller than pre-workshop by 26.9%. A radiologist-led workshop did not significantly reduce inter-observer variability in volume delineation for the three clinical sites. However, some improvement was noted in delineation of breast CTV, seroma volumes and cervix GTV.


Reciprocal immune enhancement of dengue and Zika virus infection in human skin.
Dengue virus (DENV) and Zika virus (ZIKV) are closely related mosquito-borne flaviviruses that co-circulate in tropical regions and constitute major threats to global human health. Whether preexisting immunity to one virus affects disease caused by the other during primary or secondary infections is unknown but is critical in preparing for future outbreaks and predicting vaccine safety. Using a human skin explant model, we show that DENV-3 immune sera increased recruitment and infection of Langerhans cells, macrophages, and dermal dendritic cells following inoculation with DENV-2 or ZIKV. Similarly, ZIKV immune sera enhanced infection with DENV-2. Immune sera increased migration of infected Langerhans cells to the dermis and emigration of infected cells out of skin. Heterotypic immune sera increased viral RNA in the dermis almost 10-fold and reduced the amount of virus required to infect a majority of myeloid cells by 100- to 1000-fold. Enhancement was associated with cross-reactive IgG and induction of IL-10 expression and was mediated by both CD32 and CD64 Fcγ receptors. These findings reveal that preexisting heterotypic immunity greatly enhances DENV and ZIKV infection, replication, and spread in human skin. This relevant tissue model will be valuable in assessing the efficacy and risk of dengue and Zika vaccines in humans.


Sonoanatomical Change of Phrenic Nerve According to Posture During Ultrasound-Guided Stellate Ganglion Block.
To evaluate the risk of phrenic nerve injury during ultrasound-guided stellate ganglion block (US-SGB) according to sonoanatomy of the phrenic nerve, and determine a safer posture for needle insertion by assessing its relationship with surrounding structure according to positional change. Twenty-nine healthy volunteers were recruited and underwent ultrasound in two postures, i.e., supine position with the neck extension and head rotation, and lateral decubitus position. The transducer was placed at the anterior tubercle of the C6 level to identify phrenic nerve. The cross-sectional area (CSA), depth from skin, distance between phrenic nerve and anterior tubercle of C6 transverse process, and the angle formed by anterior tubercle, posterior tubercle and phrenic nerve were measured. The phrenic nerve was clearly identified in the intermuscular fascia layer between the anterior scalene and sternocleidomastoid muscles. The distance between the phrenic nerve and anterior tubercle was 10.33±3.20 mm with the supine position and 9.20±3.31 mm with the lateral decubitus position, respectively. The mean CSA and skin depth of phrenic nerve were not statistically different between the two positions. The angle with the supine position was 48.37°±27.43°, and 58.89°±30.02° with the lateral decubitus position. The difference of angle between the two positions was statistically significant. Ultrasound is a useful tool for assessing the phrenic nerve and its anatomical relation with other cervical structures. In addition, lateral decubitus position seems to be safer by providing wider angle for needle insertion than the supine position in US-SGB.


Vortex fluidic mediated synthesis of polysulfone.
Polysulfone (PSF) was prepared under high shear in a vortex fluidic device (VFD) operating in confined mode, and its properties compared with that prepared using batch processing. This involved reacting the pre-prepared disodium salt of bisphenol A (BPA) with a 4,4'-dihalodiphenylsulfone under anhydrous conditions. Scanning electron microscopy (SEM) established that in the thin film microfluidic platform, the PSF particles are sheet-like, for short reaction times, and fibrous for long reaction times, in contrast to spherical like particles for the polymer prepared using the conventional batch synthesis. The operating parameters of the VFD (rotational speed of the glass tube, its tilt angle and temperature) were systematically varied for establishing their effect on the molecular weight (M w), glass transition temperature (T g) and decomposition temperature, featuring gel permeation chromatography (GPC), differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) respectively. The optimal VFD prepared PSF was obtained at 6000 rpm rotational speed, 45° tilt angle and 160 °C, for 1 h of processing with M w ∼10 000 g mol-1, T g ∼158 °C and decomposition temperature ∼530 °C, which is comparable to the conventionally prepared PSF.


Five-coordinate platinum(IV) complex as a precursor to a novel Pt(II) olefin hydride complex for alkane activation.
The five-coordinate platinum(IV) complex (nacnac)PtMe3 (nacnac- = [{(o-iPr2C6H3)NC(CH3)}2CH]-) thermally eliminates ethane and methane to produce a novel olefin(hydrido)platinum(II) complex, where the olefin is part of the nacnac-type ligand. This Pt(II) product activates hydrocarbons, including alkanes under mild conditions, as indicated by scrambling of hydrogen and deuterium between the hydrocarbon solvent and selected positions on the ligand of the platinum complex. A mechanism in which olefin insertion into the metal hydride bond opens a site to allow hydrocarbon coordination and C-H bond oxidative addition is proposed.


Effective microtissue RNA extraction coupled with Smart-seq2 for reproducible and robust spatial transcriptome analysis.
Spatial transcriptomics is useful for understanding the molecular organization of a tissue and providing insights into cellular function in a morphological context. In order to obtain reproducible results in spatial transcriptomics, we have to maintain tissue morphology and RNA molecule stability during the image acquisition and biomolecule collection processes. Here, we developed a tissue processing method for robust and reproducible RNA-seq from tissue microdissection samples. In this method, we suppressed RNA degradation in fresh-frozen tissue specimens by dehydration fixation and effectively collected a small amount of RNA molecules from microdissection samples by magnetic beads. We demonstrated the spatial transcriptome analysis of the mouse liver and brain in serial microdissection samples (100 μm in a diameter and 10 μm in thickness) produced by a microdissection punching system. Using our method, we could prevent RNA degradation at room temperature and effectively produce a sequencing library with Smart-seq2. This resulted in reproducible sequence read mapping in exon regions and the detection of more than 2000 genes compared to non-fixed samples in the RNA-seq analysis. Our method would be applied to various transcriptome analyses, providing the information for region specific gene expression in tissue specimens.


Risky Decision Making in Juvenile Myoclonic Epilepsy.
It is not known whether patients with juvenile myoclonic epilepsy (JME) differ from healthy people in decision making under risk, i.e., when the decision-making context offers explicit information about options, probabilities, and consequences already from the beginning. In this study, we adopted the Game of Dice Task-Double to investigate decision making under risk in a group of 36 patients with JME (mean age 25.25/SD 5.29 years) and a group of 38 healthy controls (mean age 26.03/SD 4.84 years). Participants also underwent a comprehensive neuropsychological assessment focused on frontal executive functions. Significant group differences were found in tests of psychomotor speed and divided attention, with the patients scoring lower than the controls. Importantly, patients made risky decisions more frequently than controls. In the patient group, poor decision making was associated with poor executive control, poor response inhibition, and a short interval since the last seizure episode. Executive control and response inhibition could predict 42% of variance in the frequency of risky decisions. This study indicates that patients with JME with poorer executive functions are more likely to make risky decisions than healthy controls. Decision making under risk is of major importance in every-day life, especially with regard to treatment decisions and adherence to long-term medical therapy. Since even a single disadvantageous decision may have long-lasting consequences, this finding is of high relevance.


Differences in Proinflammatory Cytokines and Monocyte Subtypes in Older as Compared With Younger Kidney Transplant Recipients.
The number of elderly patients with end-stage kidney disease requiring kidney transplantation continues to grow. Evaluation of healthy older adults has revealed proinflammatory changes in the immune system, which are posited to contribute to age-associated illnesses via "inflamm-aging." Immunologic dysfunction is also associated with impaired control of infections. Whether these immunologic changes are found in older kidney transplant recipients is not currently known, but may have important implications for risk for adverse clinical outcomes. Three months after transplant, innate immune phenotype was evaluated by flow cytometry from 60 kidney transplant recipients (22 older [≥60 years] and 38 younger [<60 years old]). Multiplex cytokine testing was used to evaluate plasma cytokine levels. Younger patients were matched to older patients based on transplant type and induction immune suppression. Older kidney transplant recipients demonstrated decreased frequency of intermediate monocytes (CD14++CD16+) compared with younger patients (1.2% vs 3.3%, P = 0.007), and a trend toward increased frequency of proinflammatory classical monocytes (CD14++CD16-) (94.5% vs 92.1%) (P = 0.065). Increased levels of interferon-gamma (IFN-γ) were seen in older patients. In this pilot study of kidney transplant recipients, we identified differences in the innate immune system in older as compared with younger patients, including increased levels of IFN-γ. This suggests that age-associated nonspecific inflammation persists despite immune suppression. The ability to apply noninvasive testing to transplant recipients will provide tools for patient risk stratification and individualization of immune suppression regimens to improve outcomes after transplantation.


Examining conscientiousness as a key resource in resisting email interruptions: Implications for volatile resources and goal achievement.
Within the context of the conservation of resources model, when a resource is deployed, it is depleted - albeit temporarily. However, when a 'key', stable resource, such as Conscientiousness, is activated (e.g., using a self-control strategy, such as resisting an email interruption), we predicted that (1) another, more volatile resource (affective well-being) would be impacted and that (2) this strategy would be deployed as a trade-off, allowing one to satisfy task goals, at the expense of well-being goals. We conducted an experience-sampling field study with 52 email-users dealing with their normal email as it interrupted them over the course of a half-day period. This amounted to a total of 376 email reported across the sample. Results were analysed using random coefficient hierarchical linear modelling and included cross-level interactions for Conscientiousness with strategy and well-being. Our first prediction was supported - deploying the stable, key resource of Conscientiousness depletes the volatile, fluctuating resource of affective well-being. However, our second prediction was not fully realized. Although resisting or avoiding an email interruption was perceived to hinder well-being goal achievement by Conscientious people, it had neither a positive nor negative impact on task goal achievement. Implications for theory and practice are discussed. It may be necessary for highly Conscientious people to turn off their email interruption alerts at work, in order to avoid the strain that results from an activation-resistance mechanism afforded by the arrival of a new email.Deploying key resources means that volatile resources may be differentially spent, depending on one's natural tendencies and how these interact with the work task and context. This suggests that the relationship between demands and resources is not always direct and predictable.Practitioners may wish to appraise the strategies they use to deal with demands such as email at work, to identify if these strategies are assisting with task or well-being goal achievement, or whether they have become defunct through automation.


Clinical effectiveness of pharmacy-led versus conventionally delivered antiviral treatment for hepatitis C in patients receiving opioid substitution therapy: a study protocol for a pragmatic cluster randomised trial.
Hepatitis C virus (HCV) infection affects 0.7% of the general population, and up to 40% of people prescribed opioid substitution therapy (OST) in Scotland. In conventional care, less than 10% of OST users are tested for HCV and less than 25% of these initiate treatment. Community pharmacists see this group frequently to provide OST supervision. This study examines whether a pharmacist-led 'test & treat' pathway increases cure rates for HCV. This protocol describes a cluster-randomised trial where 60 community pharmacies provide either conventional or pharmacy-led care. All pharmacies offer dried blood spot testing (DBST) for HCV. Participants have attended the pharmacy for OST for 3 months; are positive for HCV genotype 1 or 3; are not co-infected with HIV and/or hepatitis B; have no decompensated liver disease; are not pregnant. For conventional care, pharmacists refer HCV-positive participants to a local centre for assessment. In the pharmacy-led arm, pharmacists assess participants themselves in the pharmacy. Drug prescribing is by nurse prescribers (conventional arm) or pharmacist prescribers (pharmacy-led arm). Treatment in both arms is delivered as daily modified directly observed therapy in a pharmacy. Primary trial outcome is number of sustained virological responses at 12 weeks after treatment completion. Secondary trial outcomes are number of tests taken; treatment uptake; completion; adherence; re-infection. An economic evaluation will assess potential cost-effectiveness. Qualitative research interviews with clients and health professionals assess acceptability of a pharmacist-led pathway. This protocol has been ethically approved by the East of Scotland Research Ethics Committee 2 (15/ES/0086) and complies with the Declaration of Helsinki and principles of Good Clinical Practice. Caldicott guardian approval was given on 16 December 2016 to allow NHS Tayside to pass information to the cluster community pharmacies about the HCV test status of patients that they are seeing to provide OST supervision. NHS R&D approvals have been obtained from each health board taking part in the study. Informed consent is obtained before study enrolment and only anonymised data are stored in a secured database, enabling an audit trail. Results will be submitted to international peer-reviewed journals and presented at international conferences. NCT02706223; Pre-results.


Integrating tobacco dependence counseling into electronic dental records: a multi-method approach.
Dentistry has historically seen tobacco dependence as a medical problem. As a consequence, dentistry has not adopted or developed effective interventions to deal with tobacco dependence. With the expanded use of electronic dental records, the authors identified an opportunity to incorporate standardized expert support for tobacco dependence counseling during the dental visit. Using qualitative results from observations and focus groups, a decision support system was designed that suggested discussion topics based on the patient's desire to quit and his or her level of nicotine addiction. Because dental providers are always pressed for time, the goal was a three-minute average intervention interval. To fulfill the provider's need for an easy way to track ongoing interventions, script usage was recorded. This process helped the provider track what he or she had said to the patient about tobacco dependence during previous encounters and to vary the messages. While the individual elements of the design process were not new, the combination of them proved to be very effective in designing a usable and accepted intervention. The heavy involvement of stakeholders in all components of the design gave providers and administrators ownership of the final product, which was ultimately adopted for use in all the clinics of a large dental group practice in Minnesota.


Effect of rearing temperatures during embryonic development on the phenotypic sex in zebrafish (Danio rerio).
In zebrafish, Danio rerio, a polygenic pattern of sex determination or a female heterogamety with possible influences of environmental factors is assumed. The present study focuses on the effects of an elevated water temperature (35° C) during the embryonic development on sex determination in zebrafish. Eggs derived from 3 golden females were fertilized by the same mitotic gynogenetic male and exposed to a water temperature of 35° C, applied from 5 to 10 h post fertilization (hpf), from 5 to 24 hpf, and from 5 to 48 hpf, which correspond to the following developmental stages: gastrula, gastrula to segmentation, and gastrula to pharyngula stage, respectively. Hatching and survival rates decreased with increasing exposure to high water temperatures. Reductions in the hatching and survival rates were not responsible for differences in sex ratios. Accordingly, exposition of the fertilized eggs to a high temperature (35° C) leads to an increase of the male proportion from 22.0% in the controls to a balanced sex ratio (48.3, 47.5, and 52.6%) in the gastrula, segmentation, and pharyngula groups, respectively. These results prove the possibility to change the pathway of sexual determination during early embryonic stages in zebrafish by exposure to a high water temperature.


Parental Involvement in a School-Based Child Physical Activity and Nutrition Program in Southeastern United States: A Qualitative Analysis of Parenting Capacities.
Parent involvement varies widely in school-based programs designed to promote physical activity and healthy nutrition, yet the underlying factors that may limit parent's participation and support of learned behaviors at home are not well understood. We conducted a qualitative study that consisted of one focus group (n = 5) and 52 in-depth interviews among parents whose children participated in a school-based physical activity and nutrition (PAN) promotion program in Williamsburg, Virginia, United States. We sought to identify factors that enabled or constrained parent's support of and involvement in children's programs and to understand the underlying factors that contribute to family success in making dietary and physical activity changes at home. Parents identified their physical and mental health, self-confidence, time, and decision making as underlying "capacities" in the family health pattern. When strengthened, these capacities encourage healthful family behavior and support of school-based PAN programs. Families that succeeded in adopting lessons learned from school-based PAN programs identified four primary strategies for success: shared goals, meal planning, modeling of good behaviors, and collective activities. Interventions that aim to improve child nutrition and physical activity and the broader family health environment should consider underlying capacities of parents and the importance of joint goals and activities.


Dynamic Axonal Translation in Developing and Mature Visual Circuits.
Local mRNA translation mediates the adaptive responses of axons to extrinsic signals, but direct evidence that it occurs in mammalian CNS axons in vivo is scant. We developed an axon-TRAP-RiboTag approach in mouse that allows deep-sequencing analysis of ribosome-bound mRNAs in the retinal ganglion cell axons of the developing and adult retinotectal projection in vivo. The embryonic-to-postnatal axonal translatome comprises an evolving subset of enriched genes with axon-specific roles, suggesting distinct steps in axon wiring, such as elongation, pruning, and synaptogenesis. Adult axons, remarkably, have a complex translatome with strong links to axon survival, neurotransmission, and neurodegenerative disease. Translationally co-regulated mRNA subsets share common upstream regulators, and sequence elements generated by alternative splicing promote axonal mRNA translation. Our results indicate that intricate regulation of compartment-specific mRNA translation in mammalian CNS axons supports the formation and maintenance of neural circuits in vivo.


Quantification of patella position by ultrasound scanning and its criterion validity.
Altered position of the patella has been associated with patellofemoral joint pain. The main techniques used for assessment of position are either expensive or invasive; there are limited reports of the use of ultrasound (US) scanning to assess patella position. The aim of this study was to establish the validity of a measure of patella position using US scanning compared with those found using magnetic resonance imaging (MRI). MRI and US scans were taken of 20 subjects and analyzed using previously described methods. The correlation between patella position assessed by US scan and lateral patella displacement on MRI showed a good statistically significant correlation (r = 0.64, p = 0.003). The correlation between the patella position assessed by US scan and the equivalent measure on MRI showed an excellent statistically significant correlation (r = 0.78, p = 0.0001). The method described has shown US scanning to be a reliable measure of patella position, with strong criterion validity compared with MRI measures.


Resolving fine-scale population structure and fishery exploitation using sequenced microsatellites in a northern fish.
The resiliency of populations and species to environmental change is dependent on the maintenance of genetic diversity, and as such, quantifying diversity is central to combating ongoing widespread reductions in biodiversity. With the advent of next-generation sequencing, several methods now exist for resolving fine-scale population structure, but the comparative performance of these methods for genetic assignment has rarely been tested. Here, we evaluate the performance of sequenced microsatellites and a single nucleotide polymorphism (SNP) array to resolve fine-scale population structure in a critically important salmonid in north eastern Canada, Arctic Charr (Salvelinus alpinus). We also assess the utility of sequenced microsatellites for fisheries applications by quantifying the spatial scales of movement and exploitation through genetic assignment of fishery samples to rivers of origin and comparing these results with a 29-year tagging dataset. Self-assignment and simulation-based analyses of 111 genome-wide microsatellite loci and 500 informative SNPs from 28 populations of Arctic Charr in north-eastern Canada identified largely river-specific genetic structure. Despite large differences (~4X) in the number of loci surveyed between panels, mean self-assignment accuracy was similar with the microsatellite loci and the SNP panel (>90%). Subsequent analysis of 996 fishery-collected samples using the microsatellite panel revealed that larger rivers contribute greater numbers of individuals to the fishery and that coastal fisheries largely exploit individuals originating from nearby rivers, corroborating results from traditional tagging experiments. Our results demonstrate the efficacy of sequence-based microsatellite genotyping to advance understanding of fine-scale population structure and harvest composition in northern and understudied species.


Defining and treating the spectrum of intermediate risk nonmuscle invasive bladder cancer.
Low, intermediate and high risk categories have been defined to help guide the treatment of patients with nonmuscle invasive bladder cancer (Ta, T1, CIS). However, while low and high risk disease has been well classified, the intermediate risk category has traditionally comprised a heterogeneous group that does not fit into either of these categories. As a result, many urologists remain uncertain about the categorization of patients as intermediate risk as well as the selection of the most appropriate therapeutic option for this patient population. We review the current literature and clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer and, based on our findings, provide urologists with a better understanding of this heterogeneous risk group as well as practical recommendations for the treatment of intermediate risk patients. The IBCG analyzed published clinical trials, meta-analyses and current clinical practice guidelines on intermediate risk nonmuscle invasive bladder cancer available as of September 2013. The definitions of intermediate risk, patient outcomes and guideline recommendations were considered, as were the limitations of the available literature and additional parameters that may be useful in guiding treatment decisions in intermediate risk patients. Current definitions and management recommendations for intermediate risk nonmuscle invasive bladder cancer vary. The most simple and practical definition is that proposed by the IBCG and the AUA of multiple and/or recurrent low grade Ta tumors. The IBCG suggests that several factors should be considered in clinical decisions in intermediate risk disease, including number (greater than 1) and size (greater than 3 cm) of tumors, timing (recurrence within 1 year) and frequency (more than 1 per year) of recurrence, and previous treatment. In patients without these risk factors a single, immediate instillation of chemotherapy is advised. In those with 1 to 2 risk factors adjuvant intravesical therapy (intravesical chemotherapy or maintenance bacillus Calmette-Guérin) is recommended, and previous intravesical therapy should be considered when choosing between these adjuvant therapies. For those patients with 3 to 4 risk factors, maintenance bacillus Calmette-Guérin is recommended. It is also important that all intermediate risk patients are accurately risk stratified at initial diagnosis and during subsequent followup. This requires appropriate transurethral resection of the bladder tumor, vigilance to rule out carcinoma in situ or other potential high risk tumors, and review of histological material directly with the pathologist. Intermediate risk disease is a heterogeneous category, and there is a paucity of independent studies comparing therapies and outcomes in subgroups of intermediate risk patients. The IBCG has proposed a management algorithm that considers tumor characteristics, timing and frequency of recurrence, and previous treatment. Subgroup analyses of intermediate risk subjects in pivotal EORTC trials and meta-analyses will be important to validate the proposed algorithm and support clear evidence-based recommendations for subgroups of intermediate risk patients.


Intelligence quotient scores of 4-year-old children: social-environmental risk factors.
Verbal IQ scores in a socially heterogeneous sample of 215 4-year-old children were highly related to a cumulative environmental risk index composed of maternal, family and cultural variables. Different combinations of equal numbers of risk factors produced similar effects on IQ, providing evidence that no single factor identified here uniquely enhances or limits early intellectual achievement and that cumulative effects from multiple risk factors increase the probability that development will be compromised. The multiple risk index predicted substantially more variance in the outcome measure than did any single risk factor alone, including socioeconomic status. High-risk children were more than 24 times as likely to have IQs below 85 than low-risk children.


Nurse staffing and quality of patient care.
To assess how nurse to patient ratios and nurse work hours were associated with patient outcomes in acute care hospitals, factors that influence nurse staffing policies, and nurse staffing strategies that improved patient outcomes. MEDLINE (PubMed), CINAHL, Cochrane Databases, EBSCO research database, BioMed Central, Federal reports, National Database of Nursing Quality Indicators, National Center for Workforce Analysis, American Nurses Association, American Academy of Nurse Practitioners, and Digital Dissertations. In the absence of randomized controlled trials, observational studies were reviewed to examine the relationship between nurse staffing and outcomes. Meta-analysis tested the consistency of the association between nurse staffing and patient outcomes; classes of patient and hospital characteristics were analyzed separately. Higher registered nurse staffing was associated with less hospital-related mortality, failure to rescue, cardiac arrest, hospital acquired pneumonia, and other adverse events. The effect of increased registered nurse staffing on patients safety was strong and consistent in intensive care units and in surgical patients. Greater registered nurse hours spent on direct patient care were associated with decreased risk of hospital-related death and shorter lengths of stay. Limited evidence suggests that the higher proportion of registered nurses with BSN degrees was associated with lower mortality and failure to rescue. More overtime hours were associated with an increase in hospital related mortality, nosocomial infections, shock, and bloodstream infections. No studies directly examined the factors that influence nurse staffing policy. Few studies addressed the role of agency staff. No studies evaluated the role of internationally educated nurse staffing policies. Increased nursing staffing in hospitals was associated with lower hospital-related mortality, failure to rescue, and other patient outcomes, but the association is not necessarily causal. The effect size varied with the nurse staffing measure, the reduction in relative risk was greater and more consistent across the studies, corresponding to an increased registered nurse to patient ratio but not hours and skill mix. Estimates of the size of the nursing effect must be tempered by provider characteristics including hospital commitment to high quality care not considered in most of the studies. Greater nurse staffing was associated with better outcomes in intensive care units and in surgical patients.


Improvement in airway responsiveness and asthma severity during pregnancy. A prospective study.
In the myometrium and gut, smooth muscle becomes less contractile during pregnancy, probably because of the effect of progesterone and estrogen. It is not known whether these hormones cause similar changes in airway smooth muscle, and therefore, this study examined airway responsiveness during the large hormonal changes of pregnancy and evaluated whether changes in responsiveness are associated with changes in (1) progesterone and estrogen and (2) the clinical severity of asthma. Twenty nonpregnant asthmatic women were assessed every 3 months until conception. In the 16 who conceived, assessments were repeated once during the second and third trimesters and 1 month after delivery. Data collected preconception and from those who did not conceive within 1 yr were used for control subjects. There was a 2-fold improvement in airway responsiveness during pregnancy from a preconception mean PC20 0.35 to 0.72 mg/ml during the second trimester and 0.58 mg/ml during the third (p = 0.03). Post-delivery responsiveness (0.48 mg/ml) was not significantly different from preconception. The improvements during pregnancy were greater than the 3 monthly fluctuations when not pregnant (p = 0.04) and were greatest in those who were most hyperresponsive initially (p = 0.01). There was an associated improvement in clinical asthma severity as indicated by a reduction in minimum medication requirements (p = 0.03) and this was not at the expense of good symptoms control; both symptoms and spirometry remained unchanged during pregnancy. Changes in responsiveness were not closely related to progesterone or estriol, suggesting that other nonhormonal factors may also contribute to the improvement during pregnancy and that the control of asthmatic airway smooth muscle may not be exactly the same as that of the myometrium and gut.


Congruency in the prediction of pathogenic missense mutations: state-of-the-art web-based tools.
A remarkable degree of genetic variation has been found in the protein-encoding regions of DNA through deep sequencing of samples obtained from thousands of subjects from several populations. Approximately half of the 20 000 single nucleotide polymorphisms present, even in normal healthy subjects, are nonsynonymous amino acid substitutions that could potentially affect protein function. The greatest challenges currently facing investigators are data interpretation and the development of strategies to identify the few gene-coding variants that actually cause or confer susceptibility to disease. A confusing array of options is available to address this problem. Unfortunately, the overall accuracy of these tools at ultraconserved positions is low, and predictions generated by current computational tools may mislead researchers involved in downstream experimental and clinical studies. First, we have presented an updated review of these tools and their primary functionalities, focusing on those that are naturally prone to analyze massive variant sets, to infer some interesting similarities among their results. Additionally, we have evaluated the prediction congruency for real whole-exome sequencing data in a proof-of-concept study on some of these web-based tools.


Extinction and scattering by soft spheres.
On the basis of an approximate relation, the Mie series are replaced by new ones, which can be summed exactly with the aid of various modified and generalized forms of the addition theorem for cylindrical functions. The sums obtained simultaneously simplify the initial expressions for the scattering characteristics and preserve their analytical nature. The conventional approximations for the amplitude functions and the efficiency factors rigorously follow from the new approaches if the optical parameters are properly restricted. The acceptable domains of these approaches contain the long wavelength region and are extensive enough to study the various (including inverse) scattering problems for the real disperse systems, in which the particles are suspended in a medium with similar optical properties.


Rapid detection of SMARCB1 sequence variation using high resolution melting.
Rhabdoid tumors are rare cancers of early childhood arising in the kidney, central nervous system and other organs. The majority are caused by somatic inactivating mutations or deletions affecting the tumor suppressor locus SMARCB1 [OMIM 601607]. Germ-line SMARCB1 inactivation has been reported in association with rhabdoid tumor, epitheloid sarcoma and familial schwannomatosis, underscoring the importance of accurate mutation screening to ascertain recurrence and transmission risks. We describe a rapid and sensitive diagnostic screening method, using high resolution melting (HRM), for detecting sequence variations in SMARCB1. Amplicons, encompassing the nine coding exons of SMARCB1, flanking splice site sequences and the 5' and 3' UTR, were screened by both HRM and direct DNA sequencing to establish the reliability of HRM as a primary mutation screening tool. Reaction conditions were optimized with commercially available HRM mixes. The false negative rate for detecting sequence variants by HRM in our sample series was zero. Nine amplicons out of a total of 140 (6.4%) showed variant melt profiles that were subsequently shown to be false positive. Overall nine distinct pathogenic SMARCB1 mutations were identified in a total of 19 possible rhabdoid tumors. Two tumors had two distinct mutations and two harbored SMARCB1 deletion. Other mutations were nonsense or frame-shifts. The detection sensitivity of the HRM screening method was influenced by both sequence context and specific nucleotide change and varied from 1: 4 to 1:1000 (variant to wild-type DNA). A novel method involving digital HRM, followed by re-sequencing, was used to confirm mutations in tumor specimens containing associated normal tissue. This is the first report describing SMARCB1 mutation screening using HRM. HRM is a rapid, sensitive and inexpensive screening technology that is likely to be widely adopted in diagnostic laboratories to facilitate whole gene mutation screening.


Discriminative-stimulus effects of second generation synthetic cathinones in methamphetamine-trained rats.
Synthetic cathinones are beta-ketophenethylamine analogs manufactured to avoid legal restrictions placed on illicit stimulants like methamphetamine. Regulating these "emerging" designer drugs require scientific evidence of abuse potential. The present study evaluated the discriminative-stimulus effects of three synthetic cathinones, recently identified in commercial and confiscated products, in male Sprague-Dawley rats trained to discriminate methamphetamine (1.0 mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food delivery. Three synthetic cathinones, 4-methyl-N-ethylcathinone (4-MEC; 1.0-8.0 mg/kg), 4-methyl-alpha-pyrrolidinopropiophenone (4-MePPP; 4.0-16.0 mg/kg), and alpha-pyrrolidinopentiophenone (alpha-PVP; 0.25-2.0 mg/kg) were tested for their ability to substitute for methamphetamine. Full substitution for the training dose of methamphetamine occurred at the highest doses for both 4-MePPP and alpha-PVP, and 4-MEC did not substitute at any dose tested. The present findings show that two synthetic cathinones, 4-MePPP and alpha-PVP, produced subjective effects similar to those of methamphetamine. The synthetic cathinone, 4-MEC, did not produce subjective effects similar to those of methamphetamine with the parameters used in the current experiment. Based on findings here and by others, these three compounds warrant further tests of abuse potential.


Development of a Luminex-Based DIVA Assay for Serological Detection of African Horse Sickness Virus in Horses.
African horse sickness (AHS) is considered a fatal re-emergent vector-borne disease of horses. In the absence of any effective treatment for AHS, vaccination remains the most effective form of disease control. The new generation of vaccines, such as one based on purified, inactivated AHS virus (AHSV, serotype 4), which does not induce antibodies against non-structural protein 3 (NS3), enables the development of diagnostic methods that differentiate infected from vaccinated animals (DIVA assays). As detecting AHS in AHSV-free countries may lead to restrictions on international animal movements and thereby cause significant economic damage, these DIVA assays are crucial for reducing movement restrictions. In this article, we describe a Luminex-based multiplex assay for DIVA diagnosis of AHS, and we validate it in a duplex format to detect antibodies against structural protein 7 (VP7) and NS3 in serum samples from horses vaccinated with inactivated AHSV4 vaccine or infected with a live virus of the same serotype. Results of the Luminex-based assay for detecting anti-NS3 antibodies showed good positive correlation with results from an in-house enzyme-linked immunosorbent assay (ELISA). Thus, the Luminex-based technique described here may allow multiplex DIVA antibody detection in a single sample in less than 2 h, and it may prove adaptable for the development of robust, multiplex serological assays.


Diabetes & Women's Health (DWH) Study: an observational study of long-term health consequences of gestational diabetes, their determinants and underlying mechanisms in the USA and Denmark.
Women who experience gestational diabetes mellitus (GDM) are at exceptionally high-risk of developing type 2 diabetes (T2DM) later in life. However, limited information is available about genetic and environmental factors that are implicated in the progression from GDM to T2DM. The Diabetes & Women's Health (DWH) Study applied a hybrid design, which combined new prospective data collection with existing data in two prospective cohorts, the Danish National Birth Cohort (DNBC) and the Nurses' Health Study II (NHS II). In total, the DWH Study identified 7759 women with a GDM diagnosis from both cohorts; 4457 women participated in the DWH Study data collection, which included two cycles of follow-up from 2012 to 2014 and 2014 to 2016. Progression from GDM to T2DM was high. In the NHS II group, by 2013, 23.1% (n=846/3667) developed T2DM. In the DNBC group, at cycle 1 (2012-2014), the progression rate was even higher: 27.2% (n=215/790) had developed T2DM. Furthermore, we have shown that women who had GDM experienced a significantly greater risk of hypertension and cardiovascular diseases, as well as early stages of glomerular hyperfiltration and renal damage. Moreover, the DWH Study findings have shown that healthful diet and lifestyle factors and weight control were related to a lower risk of T2DM, hypertension and cardiovascular diseases. Primary data collection for the DWH Study is complete and investigators are currently investigating interactions of the abovementioned modifiable factors with T2DM genetic susceptibility in determining the risk of progression from GDM to T2DM. Findings from ongoing work will provide further insights for identifying more precise prevention strategies for T2DM and comorbidities in this high-risk population. Future work will examine novel biomarkers of health and disease in this cohort.


Intrapleural streptokinase for the treatment of childhood empyema.
Pleuritis with empyema is a serious complication of bacterial pneumonia, which often causes substantial morbidity and mortality among pediatric patients. Currently percutaneous catheter drainage is the mainstay therapy for loculated empyema. Intrapleural instillation of streptokinase, urokinase, and recombinant tissue plasminogen activator has been reported to facilitate the drainage of viscous fluid and fibrinous debris or multiple loculations from the pleural space of such patients. In this study, we compared with the treatments of pleural empyema by instillation of streptokinase through the chest tube and using the conventional chest tube drainage alone. We collected 21 cases from 1999 through 2005. The results of the study showed that streptokinase (SK) group patients revealed a larger volume of drainage in the beginning days of the instillation and required fewer days of drainage than tube drainage (T) group patients [8 (4.5 - 10) days vs. 16 (5.8 - 20.3) days, p = 0.02]; that the SK group patients required average 2.6 instillations. The SK patients had a shorter febrile course than the T group [12.5 (9.5 - 15.5) days vs. 16 (9.5 - 22.5) days, p = 0.14]. None of the SK patients needed additional video-assisted thoracoscopic surgery (VATS) whereas 5 patients in the T group did. The length of hospitalization in the SK group was 21.5 days and the T group patients was 24 days. Intrapleural instillation of streptokinase seldom caused clinical adverse effect and appears to be a safe adjunctive therapy to facilitate the drainage of empyema in pediatric patients. Further studies with better research design to compare the fibrinolytic agent instillation and the VATS as the first step treatment of childhood empyema are needed.


Targeting the hedgehog transcription factors GLI1 and GLI2 restores sensitivity to vemurafenib-resistant human melanoma cells.
BRAF inhibitor (BRAFi) therapy for melanoma patients harboring the V600E mutation is initially highly effective, but almost all patients relapse within a few months. Understanding the molecular mechanisms underpinning BRAFi-based therapy is therefore an important issue. Here we identified a previously unsuspected mechanism of BRAFi resistance driven by elevated Hedgehog (Hh) pathway activation that is observed in a cohort of melanoma patients after vemurafenib treatment. Specifically, we demonstrate that melanoma cell lines, with acquired in vitro-induced vemurafenib resistance, show increased levels of glioma-associated oncogene homolog 1 and 2 (GLI1/GLI2) compared with naïve cells. We also observed these findings in clinical melanoma specimens. Moreover, the increased expression of the transcription factors GLI1/GLI2 was independent of canonical Hh signaling and was instead correlated with the noncanonical Hh pathway, involving TGFβ/SMAD (transforming growth factor-β/Sma- and Mad-related family) signaling. Knockdown of GLI1 and GLI2 restored sensitivity to vemurafenib-resistant cells, an effect associated with both growth arrest and senescence. Treatment of vemurafenib-resistant cells with the GLI1/GLI2 inhibitor Gant61 led to decreased invasion of the melanoma cells in a three-dimensional skin reconstruct model and was associated with a decrease in metalloproteinase (MMP2/MMP9) expression and microphthalmia transcription factor upregulation. Gant61 monotherapy did not alter the drug sensitivity of naïve cells, but could reverse the resistance of melanoma cells chronically treated with vemurafenib. We further noted that alternating dosing schedules of Gant61 and vemurafenib prevented the onset of BRAFi resistance, suggesting that this could be a potential therapeutic strategy for the prevention of therapeutic escape. Our results suggest that targeting the Hh pathway in BRAFi-resistant melanoma may represent a viable therapeutic strategy to restore vemurafenib sensitivity, reducing or even inhibiting the acquired chemoresistance in melanoma patients.


Comparison of gross pathology inspection and 9.4 T magnetic resonance imaging in the evaluation of radiofrequency ablation lesions in the left ventricle of the swine heart.
Aims: Gross pathology inspection (patho) is the gold standard for the morphological evaluation of focal myocardial pathology. Examination with 9.4 T magnetic resonance imaging (MRI) is a new method for very accurate display of myocardial pathology. The aim of this study was to demonstrate that lesions can be measured on high-resolution MRI images with the same accuracy as on pathological sections and compare these two methods for the evaluation of radiofrequency (RF) ablation lesion dimensions in swine heart tissue during animal experiment. Methods: Ten pigs underwent radiofrequency ablations in the left ventricle during animal experiment. After animal euthanasia, hearts were explanted, flushed with ice-cold cardioplegic solution to relax the whole myocardium, fixed in 10% formaldehyde and scanned with a 9.4 T magnetic resonance system. Anatomical images were processed using ImageJ software. Subsequently, the hearts were sliced, slices were photographed and measured in ImageJ software. Different dimensions and volumes were compared. Results: The results of both methods were statistically compared. Depth by MRI was 8.771 ± 2.595 mm and by patho 9.008 ± 2.823 mm; p = 0.198. Width was 10.802 ± 2.724 mm by MRI and 11.125 ± 2.801 mm by patho; p = 0.049. Estuary was 2.006 ± 0.867 mm by MRI and 2.001 ± 0.872 mm by patho; p = 0.953. The depth at the maximum diameter was 4.734 ± 1.532 mm on MRI and 4.783 ± 1.648 mm from the patho; p = 0.858. The volumes of the lesions calculated using a formula were 315.973 ± 257.673 mm3 for MRI and 355.726 ± 255.860 mm3 for patho; p = 0.104. Volume directly measured from MRI with the "point-by-point" method was 671.702 ± 362.299 mm3. Conclusion: Measurements obtained from gross pathology inspection and MRI are fully comparable. The advantage of MRI is that it is a non-destructive method enabling repeated measurements in all possible anatomical projections.


Pulmonary Carcinoid Surface Receptor Modulation Using Histone Deacetylase Inhibitors.
Pulmonary carcinoids are a type of neuroendocrine tumor (NET) accounting for 1-2% of lung cancer cases. Currently, Positron Emission Tomography (PET)/CT based on the radiolabeled sugar analogue [18F]-FDG is used to diagnose and stage pulmonary carcinoids, but is suboptimal due to low metabolic activity in these tumors. A new technique for pulmonary carcinoid imaging, using PET/CT with radiolabeled somatostatin analogs that specifically target somatostatin receptor subtype 2 (SSTR2), is becoming more standard, as many tumors overexpress SSTR2. However, pulmonary carcinoid patients with diminished SSTR2 expression are not eligible for this imaging or any type of SSTR2-specific treatment. We have found that histone deacetylase (HDAC) inhibitors can upregulate the expression of SSTR2 in pulmonary carcinoid cell lines. In this study, we used a non-cytotoxic dose of HDAC inhibitors to induce pulmonary carcinoid SSTR2 expression in which we confirmed in vitro and in vivo. A non-cytotoxic dose of the HDAC inhibitors: thailandepsin A (TDP-A), romidepsin (FK228), suberoylanilide hydroxamic acid (SAHA), AB3, and valproic acid (VPA) were administered to promote SSTR2 expression in pulmonary carcinoid cell lines and xenografts. This SSTR2 upregulation technique using HDAC inhibitors could enhance radiolabeled somatostatin analog-based imaging and the development of potential targeted treatments for pulmonary carcinoid patients with marginal or diminished SSTR2 expression.


Metabolic and signalling network maps integration: application to cross-talk studies and omics data analysis in cancer.
The interplay between metabolic processes and signalling pathways remains poorly understood. Global, detailed and comprehensive reconstructions of human metabolism and signalling pathways exist in the form of molecular maps, but they have never been integrated together. We aim at filling in this gap by integrating of both signalling and metabolic pathways allowing a visual exploration of multi-level omics data and study of cross-regulatory circuits between these processes in health and in disease. We combined two comprehensive manually curated network maps. Atlas of Cancer Signalling Network (ACSN), containing mechanisms frequently implicated in cancer; and ReconMap 2.0, a comprehensive reconstruction of human metabolic network. We linked ACSN and ReconMap 2.0 maps via common players and represented the two maps as interconnected layers using the NaviCell platform for maps exploration ( https://navicell.curie.fr/pages/maps_ReconMap%202.html ). In addition, proteins catalysing metabolic reactions in ReconMap 2.0 were not previously visually represented on the map canvas. This precluded visualisation of omics data in the context of ReconMap 2.0. We suggested a solution for displaying protein nodes on the ReconMap 2.0 map in the vicinity of the corresponding reaction or process nodes. This permits multi-omics data visualisation in the context of both map layers. Exploration and shuttling between the two map layers is possible using Google Maps-like features of NaviCell. The integrated networks ACSN-ReconMap 2.0 are accessible online and allows data visualisation through various modes such as markers, heat maps, bar-plots, glyphs and map staining. The integrated networks were applied for comparison of immunoreactive and proliferative ovarian cancer subtypes using transcriptomic, copy number and mutation multi-omics data. A certain number of metabolic and signalling processes specifically deregulated in each of the ovarian cancer sub-types were identified. As knowledge evolves and new omics data becomes more heterogeneous, gathering together existing domains of biology under common platforms is essential. We believe that an integrated ACSN-ReconMap 2.0 networks will help in understanding various disease mechanisms and discovery of new interactions at the intersection of cell signalling and metabolism. In addition, the successful integration of metabolic and signalling networks allows broader systems biology approach application for data interpretation and retrieval of intervention points to tackle simultaneously the key players coordinating signalling and metabolism in human diseases.


Visualization of the core-scattering dynamics of Rydberg wave packets.
We present classical and quantum studies of the scattering dynamics of Rydberg electron wave packets from the electronic core of alkali atoms. In quantum systems an ideal state for studying such effects is an angularly localized wavepacket in which the primary effect of the scattering is to cause precession. The scattering is enhanced by the application of an external dc electric field. We calculate and animate the field-induced dynamics of both hydrogenic and alkali wavepackets and compare them to classical atomic models. We end that in alkali systems the scattered wave function can be divided into two components: one whose nearly hydrogenic behavior is due to quantum interference near the core, and another which exhibits the orbital precession found in classical models of nonhydrogenic atoms.


Mixed-valence [Fe(I)Fe(II)] hydrogenase active site model complexes stabilized by a bidentate carborane bis-phosphine ligand.
A series of [FeFe]-hydrogenase active site analogues, with the general formula [Fe(2)(dt)(CO)(4)(BC)] 1-3 (dt = dithiolate, pdt = propyl-1,3-dt (1), bdt = benzene-1,2-dt (2), edt = ethyl-1,2-dt (3); BC = 1,2-bisdiphenylphosphine-1,2-o-carborane), has been prepared and structurally characterized. While the electrochemical reductions of 1-3 are largely invariant to the different nature of their dt bridges, the oxidations differ by more than 120 mV in between the series. Remarkably, all three compounds are reversibly oxidized, with complex 1 that contains the most electron-donating pdt ligand at the mildest potential of -0.09 V vs. Fc/Fc(+). The one-electron oxidized state 1(ox) is stable for several minutes and was spectroscopically characterized by FTIR and EPR. EPR spectroscopy provided evidence that in the mixed-valence [Fe(I)Fe(II)] state most of the spin density is located on the iron with the BC-ligand. This is monitored through the strong (31)P hyperfine coupling of the phenyl groups of the BC ligand, while further delocalization into the o-carborane unit is negligible.


Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes.
Bile acids (BAs) are important gut signaling hormones, influencing lipid, glucose, and energy homeostasis. The exact mechanisms behind these effects are not yet fully understood. Lately, they have come to the fore as putative therapeutics in metabolic diseases, such as e.g. nonalcoholic fatty liver disease (NAFLD). We elucidate to what extent BAs impacts on the mRNAome and microRNAome in hepatocytes to gather novel insights into the mechanisms behind metabolic and toxicologic effects of bile acids. Five batches of primary human hepatocytes were treated with 50μmol/l chenodeoxycholic acid (CDCA) for 24 or 48h. Total RNA was extracted, size fractionated and subjected to Next Generation Sequencing to generate mRNA and miRNA profiles. Expression of 738 genes and 52 miRNAs were CDCA dependently decreased, whereas 1566 genes and 29 miRNAs were significantly increased in hepatocytes. Distinct gene clusters controlling BA and lipid homeostasis (FGF(R), APO and FABP family members, HMGCS2) and drug metabolism (CYP, UGT and SULT family members) were significantly modulated by CDCA. Importantly, CDCA affected distinct microRNAs, including miR-34a, -505, -885, -1260 and -552 that systematically correlated in expression with gene clusters responsible for bile acid, lipid and drug homeostasis incorporating genes, such as e.g. SLCO1B1, SLC22A7, FGF19, CYP2E1, CYP1A2, APO family members and FOXO3. Bile acids significantly modulate metabolic and drug associated gene networks that are connected to distinct shifts in the microRNAome These findings give novel insights on how BA enfold metabolic and system toxic effects.


Progress and prospects: Immunobiology of gene therapy for neurodegenerative disease: prospects and risks.
Gene therapy for neurological, and in particular neurodegenerative, disease is now a reality. A number of early phase clinical trials have been completed and several are currently in progress. In view of this, it is critically important to evaluate the immunological risk associated with neurological gene therapy, which has clear implications for trial safety and efficacy. Moreover, it is imperative in particular to identify factors indicating potential high risk. In the light of recent advances in understanding immune regulation in the central nervous system (CNS) and with the continued development of new gene delivery vectors, this review critically assesses the current knowledge of immunobiology within the CNS in terms of likely immunological risk pertaining to viral vectors and gene therapy applications for neurodegenerative disease.


Understanding the Strength of the Selenium-Graphene Interfaces for Energy Storage Systems.
We present comprehensive first-principles density functional theory (DFT) analyses of the interfacial strength and bonding mechanisms between crystalline and amorphous selenium (Se) with graphene (Gr), a promising duo for energy storage applications. Comparative interface analyses are presented on amorphous silicon (Si) with graphene and crystalline Se with a conventional aluminum (Al) current collector. The interface strengths of monoclinic Se (0.43 J m-2) and amorphous Si with graphene (0.41 J m-2) are similar in magnitude. While both materials (c-Se, a-Si) are bonded loosely by van der Waals (vdW) forces over graphene, interfacial electron exchange is higher for a-Si/graphene. This is further elaborated by comparing the potential energy step and charge transfer (Δq) across the graphene interfaces. The interface strength of c-Se on a 3D Al current collector is higher (0.99 J m-2), suggesting a stronger adhesion. Amorphous Se with graphene has comparable interface strength (0.34 J m-2), but electron exchange in this system is slightly distinct from monoclinic Se. The electronic characteristics and bonding mechanisms are different for monoclinic and amorphous Se with graphene as they activate graphene via surface charge doping divergently. The implications of these interfacial physicochemical attributes on electrode performance have been discussed. Our findings highlight the complex electrochemical phenomena in Se interfaced with graphene, which may profoundly differ from their "free" counterparts.