Genome-Wide Meta-Analyses of FTND and TTFC Phenotypes.
FTND (Fagerstrӧm test for nicotine dependence) and TTFC (time to smoke first cigarette in the morning) are common measures of nicotine dependence (ND). However, genome-wide meta-analysis for these phenotypes has not been reported. Genome-wide meta-analyses for FTND (N = 19,431) and TTFC (N = 18,567) phenotypes were conducted for adult smokers of European ancestry from 14 independent cohorts. We found that SORBS2 on 4q35 (p = 4.05 × 10-8), BG182718 on 11q22 (p = 1.02 × 10-8), and AA333164 on 14q21 (p = 4.11 × 10-9) were associated with TTFC phenotype. We attempted replication of leading candidates with independent samples (FTND, N = 7010 and TTFC, N = 10 061), however, due to limited power of the replication samples, the replication of these new loci did not reach significance. In gene-based analyses, COPB2 was found associated with FTND phenotype, and TFCP2L1, RELN, and INO80C were associated with TTFC phenotype. In pathway and network analyses, we found that the interconnected interactions among the endocytosis, regulation of actin cytoskeleton, axon guidance, MAPK signaling, and chemokine signaling pathways were involved in ND. Our analyses identified several promising candidates for both FTND and TTFC phenotypes, and further verification of these candidates was necessary. Candidates supported by both FTND and TTFC (CHRNA4, THSD7B, RBFOX1, and ZNF804A) were associated with addiction to alcohol, cocaine, and heroin, and were associated with autism and schizophrenia. We also identified novel pathways involved in cigarette smoking. The pathway interactions highlighted the importance of receptor recycling and internalization in ND. Understanding the genetic architecture of cigarette smoking and ND is critical to develop effective prevention and treatment. Our study identified novel candidates and biological pathways involved in FTND and TTFC phenotypes, and this will facilitate further investigation of these candidates and pathways.


Intraterminal recordings from the rat neurohypophysis in vitro.
1. Intracellular recordings were obtained from neurosecretory terminals (endings of Herring bodies), axons and pars intermedia cells in the isolated neuro-intermediate lobe of the rat. Responses to current injection and stimulation of the neural stalk (NS) were examined at 34 degrees C. Cellular identity was verified following injection of Lucifer Yellow. 2. Neurosecretory terminals were identified by a constant-latency action potential response to NS stimulation and an appropriate collision test. This response was not blocked by Ca2(+)-free solutions. Hyperpolarization of the terminals could block the generation of a local spike. Injection of Lucifer Yellow into eleven units confirmed that such responses were recorded from neurosecretory terminals. 3. Neurohypophysial nerve terminals had a resting potential of -60.4 +/- 1.1 mV and displayed a spike amplitude of 72.4 +/- 1.9 mV. The local spike threshold was -41.6 +/- 1.9 mV. Voltage-current relations were linear near resting potential, but displayed strong outward rectification positive to -55 mV. While terminals could fire at high frequencies during NS stimulation, repetitive activity could not be evoked by prolonged depolarizing current pulses. 4. During the initial 1-3 s of a train of brief depolarizing pulses or NS stimuli, nerve terminals showed a progressive broadening of their action potentials. At steady state, the duration of these impulses increased logarithmically with firing rate, showing a maximum near 25 Hz. Spike broadening in nerve terminals was reversibly abolished by superfusion of the neural lobe with Ca2(+)-free, Mn2(+)-containing solutions. In the absence of external Ca2+, action potentials were smaller, and lacked a prominent shoulder on their repolarizing phase. 5. Sustained (greater than 5 s) repetitive stimulation at 10-20 Hz led to a gradual increase in the latency for invasion and eventual failure of the spike-generating mechanism within the terminal. This effect required several seconds to recover. In contrast, action potentials recorded within the axon followed continuous repetitive stimulation and did not show any frequency-dependent changes in duration (0.7 +/- 0.1 ms). 6. Cells of the pars intermedia (PI) displayed an input resistance of 215.7 +/- 47.4 M omega and fired a single action potential in response to current injection. The amplitude of this current-evoked spike decreased during repetitive stimulation, but its duration was not affected. In 87% of the PI cells tested, stimulation of the NS evoked a Ca2(+)-sensitive synaptic response which reversed near -40 mV, but no cell was directly activated by the stimulus.


Non-equilibrium molecular dynamics simulations of the transient Ludwig-Soret effect in a binary Lennard-Jones/spline mixture.
A binary isotope mixture of Lennard-Jones/spline particles at equilibrium was perturbed by a sudden change in the system's boundary temperatures. The system's response was determined by non-equilibrium molecular dynamics (NEMD). Three transient processes were studied: 1) The propagation of a pressure (shock) wave, 2) heat diffusivity and conduction, and 3) thermal diffusion (the Ludwig-Soret effect). These three processes occur at different time scales, which makes it possible to separate them in one single NEMD run. The system was studied in liquid, supercritical, and dense gas states with various forms and strengths of the thermal perturbation. The results show that heat was initially transported by two separate mechanisms: 1) heat diffusion as described by the transient heat equation and 2) as a consequence of a pressure wave. The pressure wave travelled faster than the speed of sound, generating a shock wave in the system. Local equilibrium was found in the transient phase, even with very strong perturbations and in the shock front. Although the mass separation due to the Ludwig-Soret effect developed much slower than the pressure and temperature fields in the system at large, it was found that the Soret coefficient could be accurately determined from the initial phase of the transient and close to the heat source. This opens the possibility of a new way to analyse results from transient experiments and thereby minimize effects of gravity and convection due to buoyancy.


Genomewide Assessment of Mycobacterium tuberculosis Conditionally Essential Metabolic Pathways.
A better understanding of essential cellular functions in pathogenic bacteria is important for the development of more effective antimicrobial agents. We performed a comprehensive identification of essential genes in Mycobacterium tuberculosis, the major causative agent of tuberculosis, using a combination of transposon insertion sequencing (Tn-seq) and comparative genomic analysis. To identify conditionally essential genes by Tn-seq, we used media with different nutrient compositions. Although many conditional gene essentialities were affected by the presence of relevant nutrient sources, we also found that the essentiality of genes in a subset of metabolic pathways was unaffected by metabolite availability. Comparative genomic analysis revealed that not all essential genes identified by Tn-seq were fully conserved within the M. tuberculosis complex, including some existing antitubercular drug target genes. In addition, we utilized an available M. tuberculosis genome-scale metabolic model, iSM810, to predict M. tuberculosis gene essentiality in silico Comparing the sets of essential genes experimentally identified by Tn-seq to those predicted in silico reveals the capabilities and limitations of gene essentiality predictions, highlighting the complexity of M. tuberculosis essential metabolic functions. This study provides a promising platform to study essential cellular functions in M. tuberculosis IMPORTANCE Mycobacterium tuberculosis causes 10 million cases of tuberculosis (TB), resulting in over 1 million deaths each year. TB therapy is challenging because it requires a minimum of 6 months of treatment with multiple drugs. Protracted treatment times and the emergent spread of drug-resistant M. tuberculosis necessitate the identification of novel targets for drug discovery to curb this global health threat. Essential functions, defined as those indispensable for growth and/or survival, are potential targets for new antimicrobial drugs. In this study, we aimed to define gene essentialities of M. tuberculosis on a genomewide scale to comprehensively identify potential targets for drug discovery. We utilized a combination of experimental (functional genomics) and in silico approaches (comparative genomics and flux balance analysis). Our functional genomics approach identified sets of genes whose essentiality was affected by nutrient availability. Comparative genomics revealed that not all essential genes were fully conserved within the M. tuberculosis complex. Comparing sets of essential genes identified by functional genomics to those predicted by flux balance analysis highlighted gaps in current knowledge regarding M. tuberculosis metabolic capabilities. Thus, our study identifies numerous potential antitubercular drug targets and provides a comprehensive picture of the complexity of M. tuberculosis essential cellular functions.


Mortality attributable to obesity among middle-aged adults in the United States.
Obesity is considered a major cause of premature mortality and a potential threat to the longstanding secular decline in mortality in the United States. We measure relative and attributable risks associated with obesity among middle-aged adults using data from the Health and Retirement Study (1992-2004). Although class II/III obesity (BMI > or = or = 35.0 kg/m2) increases mortality by 40% in females and 62% in males compared with normal BMI (BMI = 18.5-24.9), class I obesity (BMI = 30.0-34.9) and being overweight (BMI = 25.0-29.9) are not associated with excess mortality. With respect to attributable mortality, class II/III obesity (BMI > or = 35.0) is responsible for approximately 4% of deaths among females and 3% of deaths among males. Obesity is often compared with cigarette smoking as a major source of avoidable mortality. Smoking-attributable mortality is much larger in this cohort: about 36% in females and 50% in males. Results are robust to confounding by preexisting diseases, multiple dimensions of socioeconomic status (SES), smoking, and other correlates. These findings challenge the viewpoint that obesity will stem the long-term secular decline in U.S. mortality.


Transcription factor-dependent nuclear localization of a transcriptional repressor in jasmonate hormone signaling.
The plant hormone jasmonate (JA) plays an important role in regulating growth, development and immunity. A key step in JA signaling is ligand-dependent assembly of a coreceptor complex consisting of the F-box protein COI1 and JAZ transcriptional repressors. Assembly of this receptor complex results in proteasome-mediated degradation of JAZ repressors, which at resting state bind to and repress the MYC transcription factors. Although the JA receptor complex is believed to function within the nucleus, how this receptor complex enters the nucleus and, more generally, the cell biology of jasmonate signaling are not well understood. In this study, we conducted mutational analysis of the C termini (containing the conserved Jas motif) of two JAZ repressors, JAZ1 and JAZ9. These analyses unexpectedly revealed different subcellular localization patterns of JAZ1ΔJas and JAZ9ΔJas, which were associated with differential interaction of JAZ1ΔJas and JAZ9ΔJas with MYC2 and differential repressor activity in vivo. Importantly, physical interaction with MYC2 appears to play an active role in the nuclear targeting of JAZ1 and JAZ9, and the nuclear localization of JAZ9 was compromised in myc2 mutant plants. We identified a highly conserved arginine residue in the Jas motif that is critical for coupling MYC2 interaction with nuclear localization of JAZ9 and JAZ9 repressor function in vivo. Our results suggest a model for explaining why some JAZΔJas proteins, but not others, confer constitutive JA-insensitivity when overexpressed in plants. Results also provide evidence for a transcription factor-dependent mechanism for nuclear import of a cognate transcriptional repressor JAZ9 in plants.


An algorithm for the management of restless legs syndrome.
Restless legs syndrome (RLS) is a common disorder with a prevalence of 5% to 15%. Primary care physicians must become familiar with management of this disorder. This algorithm for the management of RLS was written by members of the Medical Advisory Board of the Restless Legs Syndrome Foundation and is based on scientific evidence and expert opinion. Restless legs syndrome is divided into intermittent, daily, and refractory types. Nonpharmacological approaches, including mental alerting activities, avoiding substances or medications that may exacerbate RLS, and addressing the possibility of iron deficiency, are discussed. The role of carbidopa/levodopa, dopamine agonists, opioids, benzodiazepines, and anticonvulsants for the different types of the disorder is delineated.


Doubly robust evaluation of high-dimensional surrogate markers.
When evaluating the effectiveness of a treatment, policy, or intervention, the desired measure of efficacy may be expensive to collect, not routinely available, or may take a long time to occur. In these cases, it is sometimes possible to identify a surrogate outcome that can more easily, quickly, or cheaply capture the effect of interest. Theory and methods for evaluating the strength of surrogate markers have been well studied in the context of a single surrogate marker measured in the course of a randomized clinical study. However, methods are lacking for quantifying the utility of surrogate markers when the dimension of the surrogate grows. We propose a robust and efficient method for evaluating a set of surrogate markers that may be high-dimensional. Our method does not require treatment to be randomized and may be used in observational studies. Our approach draws on a connection between quantifying the utility of a surrogate marker and the most fundamental tools of causal inference-namely, methods for robust estimation of the average treatment effect. This connection facilitates the use of modern methods for estimating treatment effects, using machine learning to estimate nuisance functions and relaxing the dependence on model specification. We demonstrate that our proposed approach performs well, demonstrate connections between our approach and certain mediation effects, and illustrate it by evaluating whether gene expression can be used as a surrogate for immune activation in an Ebola study.


Evaluation of mechanical transmission of HIV by the African soft tick, Ornithodoros moubata.
To assess the ability of the African Hut Tampan, Ornithodoros moubata, to mechanically transmit HIV-1 and to re-appraise HIV-1 infectivity in an arthropod cell line at 28 and 35 degrees C. To evaluate HIV-1 transmission by O. moubata, as determined by HIV-1 survival, 'blood-meal' size and interval between feeds, various tick developmental stages were allowed to feed on a heavily infected lymphoblast-rich blood-meal containing HIV-1BRU in an in vitro feeding chamber. Blood-meal regurgitation was evaluated using 51Cr-labelled human erythrocytes, and human lymphoblast survival in ticks using Trypan blue. HIV-1 survival in ticks was evaluated by reverse transcriptase activity in tick homogenates cocultured with CEM lymphoblasts. Polymerase chain reaction and Southern blot analysis were used to detect proviral HIV-1 in arthropod cells in vitro. HIV-1BRU remained viable for up to 10 days with O. moubata adults. This is the longest recorded survival of HIV in an arthropod. In agreement with other studies. O. moubata regurgitated part of its previous blood-meal into the feeding lesion. Human CEM lymphoblasts partially survived for up to 7 days at 28 and 35 degrees C inside O. moubata's digestive tract. The blood-meal of adult female ticks was as high as 240 microliters (approximately 70 times more than a mosquito), while the most likely potential mechanical vectors (fourth- and fifth-stage nymphs) ingested an average of 39 microliters (maximum, 73 microliters), with some ticks re-feeding as early as 14 days postfeed in the absence of a moult. Shortcomings associated with the experimental protocol suggest that HIV survival within O. moubata may reach 14 days following natural infection, or that ticks might re-feed earlier. Although HIV-1BRU and HIV-1NDK were unable to replicate at 28 and 35 degrees C in CD4- Aedes albopictus C6/36 mosquito cells, HIV-1NDK was detected in its proviral form. Our investigations showed that mechanical transmission of HIV-1 by O. moubata is unlikely to occur in the laboratory. This may not be the situation under field conditions.


Automating data citation: the eagle-i experience.
Data citation is of growing concern for owners of curated databases, who wish to give credit to the contributors and curators responsible for portions of the dataset and enable the data retrieved by a query to be later examined. While several databases specify how data should be cited, they leave it to users to manually construct the citations and do not generate them automatically. We report our experiences in automating data citation for an RDF dataset called eagle-i, and discuss how to generalize this to a citation framework that can work across a variety of different types of databases (e.g. relational, XML, and RDF). We also describe how a database administrator would use this framework to automate citation for a particular dataset.


Caffeine withdrawal and high-intensity endurance cycling performance.
In this study, we investigated the impact of a controlled 4-day caffeine withdrawal period on the effect of an acute caffeine dose on endurance exercise performance. Twelve well-trained and familiarized male cyclists, who were caffeine consumers (from coffee and a range of other sources), were recruited for the study. A double-blind placebo-controlled cross-over design was employed, involving four experimental trials. Participants abstained from dietary caffeine sources for 4 days before the trials and ingested capsules (one in the morning and one in the afternoon) containing either placebo or caffeine (1.5 mg · kg(-1) body weight · day(-1)). On day 5, capsules containing placebo or caffeine (3 mg · kg(-1) body weight) were ingested 90 min before completing a time trial, equivalent to one hour of cycling at 75% peak sustainable power output. Hence the study was designed to incorporate placebo-placebo, placebo-caffeine, caffeine-placebo, and caffeine-caffeine conditions. Performance time was significantly improved after acute caffeine ingestion by 1:49 ± 1:41 min (3.0%, P = 0.021) following a withdrawal period (placebo-placebo vs. placebo-caffeine), and by 2:07 ± 1:28 min (3.6%, P = 0.002) following the non-withdrawal period (caffeine-placebo vs. caffeine-caffeine). No significant difference was detected between the two acute caffeine trials (placebo-caffeine vs. caffeine-caffeine). Average heart rate throughout exercise was significantly higher following acute caffeine administration compared with placebo. No differences were observed in ratings of perceived exertion between trials. A 3 mg · kg(-1) dose of caffeine significantly improves exercise performance irrespective of whether a 4-day withdrawal period is imposed on habitual caffeine users.


Regular Aerobic Voluntary Exercise Increased Oxytocin in Female Mice: The Cause of Decreased Anxiety and Increased Empathy-Like Behaviors
It is known that regular physical activity reduces anxiety. Low anxiety levels affect mood, emotions, and empathy. Oxytocin is a powerful hormone that regulates social interaction, sexual reproduction, maternal–infant bonding, milk release, empathy, and anxiety. Empathy is an important behavior in the living community; and also important for sportsmen during sportive competition and daily living life, because sportsmen are also role model of people. To investigate the effects of voluntary physical activity on oxytocin, anxiety, and empathy levels as well as the relationship between them. Animal experiment. Male and female mice were made to exercise in running wheel cages for 6 weeks. Their empathy and anxiety levels were evaluated by using Helping Behavior test and elevated plus maze and open field test, respectively. And then the brain and blood oxytocin levels were measured. Empathy-like behavior was improved in both genders of the exercise groups (door-opening time decreased in both genders of exercise groups, p for both=0.0001). As a response to exercise, both the brain and serum oxytocin levels increased in female mice (both of p=0.0001); however, in males, oxytocin levels increased in only the brain (p<0.05). Anxiety levels decreased in all the exercise groups (increased time spent in the middle area of open field test, both genders, p=0.002; increased time spent in the open arms of elevated plus maze test, females p=0.004, males p=0.0001). There was a strong negative correlation between serum oxytocin levels and door opening time of helping behavior equipment, and moderate negative correlation was found between the brain oxytocin levels and door-opening time of helping behavior equipment in females. However, there was no correlation between both the brain and serum oxytocin levels and empathy behavior in males. But there were very strong positive correlations between low anxiety indicators and both the brain and serum oxytocin levels in both the genders. Voluntary physical activity decreases anxiety and increases empathy-like behavior in mice; which is associated with increased oxytocin levels in female mice but not in male mice. Further research is required to investigate the mechanisms of exercise effect on anxiety and empathic brain pathways in males.


Large protein organelles form a new iron sequestration system with high storage capacity.
Iron storage proteins are essential for cellular iron homeostasis and redox balance. Ferritin proteins are the major storage units for bioavailable forms of iron. Some organisms lack ferritins, and it is not known how they store iron. Encapsulins, a class of protein-based organelles, have recently been implicated in microbial iron and redox metabolism. Here, we report the structural and mechanistic characterization of a 42 nm two-component encapsulin-based iron storage compartment from Quasibacillus thermotolerans. Using cryo-electron microscopy and x-ray crystallography, we reveal the assembly principles of a thermostable T = 4 shell topology and its catalytic ferroxidase cargo and show interactions underlying cargo-shell co-assembly. This compartment has an exceptionally large iron storage capacity storing over 23,000 iron atoms. Our results reveal a new approach for survival in diverse habitats with limited or fluctuating iron availability via an iron storage system able to store 10 to 20 times more iron than ferritin.


Renal telemedicine through video-as-a-service delivered to patients on home dialysis: A qualitative study on the renal care team members' experience.
The Lancashire Teaching Hospitals NHS Trust in the UK has been providing renal care through video-as-a-service (VAAS) to patients since 2013, with support from the North West NHS Shared Infrastructure Service, a collaborative team that supports information and communication technology use in the UK National Health Service. Renal telemedicine offered remotely to patients on home dialysis supports renal care through the provision of a live high-quality video link directly to unsupported patients undergoing haemodialysis at home. Home haemodialysis is known to provide benefits to patients, particularly in making them more independent. The use of a telemedicine video-link in Lancashire and South Cumbria, UK, further reduces patient dependence on the professional team. The purpose of this paper is to present the perspectives of the renal care team members using the renal telemedicine service to understand the perceived benefits and issues with the service. Ten semi-structured interviews with members of the renal care team (two renal specialists, one matron, two renal nurses, one business manager, one renal technical services manager, two IT technicians and one hardware maintenance technician) were conducted. Thematic analysis was undertaken to analyse the qualitative data. A range of incremental benefits to the renal team members were reported, including more efficient use of staff time, reduced travel, peace of mind and a strong sense of job satisfaction. Healthcare staff believed that remote renal care through video was useful, encouraged concordance and could nurture confidence in patients. Key technological issues and adjustments which would improve the renal telemedicine service were also identified. The impact of renal telemedicine was positive on the renal team members. The use of telemedicine has been demonstrated to make home dialysis delivery more efficient and safe. The learning from staff feedback could inform development of services elsewhere.


Parasitological, serological, and clinical studies of Wuchereria bancrofti in Limbe, Haiti.
A survey for Wuchereria bancrofti in Limbe, Haiti (est. pop. = 10,500) revealed that 17% (231/1,450) had a patent infection. Nearly half of those surveyed harbored fewer than 10 microfilariae (mf) per 20 mm3 of finger-prick blood; the median mf density for females and males was 12.4 and 9.5, respectively. Parasitemias occurred as early as age 4. Antibody titers greater than or equal to 1:20 against adult D. viteae antigen were observed in 38% of microfilaremic individuals and in 29% of amicrofilaremic individuals. Peak antibody responsiveness (40%) was observed between 5 and 9 years of age. In all age groups there was no correlation between mf density and antibody titer. Among the mf carriers, 5.6% had no clinical symptoms. Lymphangitis was a common feature with 14.3% having lymphedema, 8.2% with edema of the lower extremities, and 1.3% reporting episodes of chyluria. Genital involvement among women was rare, but in males 5.4% had genital swelling and 4.5% had hydroceles. Culex pipiens quinquefasciatus (Say) was observed to support the complete development of W. bancrofti in Limbe.


Detecting the adsorption of dye molecules in homogeneous poly(propylene imine) dendrimer monolayers by surface plasmon resonance sensor.
In this work, we studied guest-host interactions between various dye molecules and the fifth-generation poly(propylene imine) (PPI-5) dendrimers in aqueous solutions using a surface plasmon resonance (SPR) sensor. The effect of the properties of guest and host molecules (e.g., charge and shape) and media (e.g., pH and ion strength) on affinity between guest and host molecules was investigated. Based on an immobilized homogeneous monolayer of PPI-5 dendrimer tethered to carboxyl-terminal self-assembled monolayers, the adsorption behavior of a group of dye molecules in PPI-5 was obtained. Results show that the strong affinity of PPI-5 to Rose Bengal and erythrosine B is attributed to the good match in charge and shape between the cavities of the dendrimer and the dye molecules. Maximum adsorption around a pH value of 7 was observed. The kinetic behaviors of different dye molecules in dendrimers were also studied. A fundamental understanding of guest-host interactions in dendrimers will guide the design of new-generation sensors and drug delivery carriers.


(23)Na multiple-quantum MAS NMR of the perovskites NaNbO(3) and NaTaO(3).
The distorted perovskites NaTaO(3) and NaNbO(3) have been studied using (23)Na multiple-quantum (MQ) MAS NMR. NaTaO(3) was prepared by high temperature solid state synthesis and the NMR spectra are consistent with the expected room temperature structure of the material (space group Pbnm), with a single crystallographic sodium site. Two samples of NaNbO(3) were studied. The first, a commercially available sample which was annealed at 900 degrees C, showed two crystallographic sodium sites, as expected for the room temperature structure of the material (space group Pbcm). The second sample, prepared by a low temperature hydrothermal method, showed the presence of four sodium sites, two of which match the expected room temperature structure and the second pair, another polymorph of the material (space group P21ma). This is consistent with powder X-ray diffraction data which showed weak extra peaks which can be accounted for by the presence of this second polymorph. Density functional theory (DFT) calculations support our conclusions, and aid assignment of the NMR spectra. Finally, we discuss the measured NMR parameters in relation to other studies of sodium in high coordination sites in the solid state.


Sensitivity and specificity of the macimorelin test for diagnosis of AGHD.
The macimorelin test is approved for the diagnosis of adult growth hormone deficiency (AGHD) based on its efficacy vs the insulin tolerance test (ITT). Macimorelin has a significant advantage over ITT in avoiding hypoglycemia. Analyses were conducted to determine whether macimorelin performance is affected by age, BMI, or sex, and evaluate its performance vs ITT over a range of GH cutpoints. Post hoc analyses of data from a previous randomized phase 3 study included participants aged 18-66 years with BMI <37 kg/m2 and high (Group A), intermediate (Group B), or low (Group C) likelihood for AGHD based on pituitary history, and matched controls (Group D). Probability of AGHD was estimated using unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted logistic models. Area under the curve (AUC) of the estimated receiver operating characteristic (ROC) curve (range, 0-1; 1 = perfect) was compared for adjusted vs unadjusted models. Separate analyses evaluated agreement, sensitivity, and specificity for macimorelin and ITT using cutpoints of 2.8, 4.0, 5.1, and 6.5 ng/mL. For participants in Group A (n = 41) and Group D (n = 29), unadjusted, age-adjusted, BMI-adjusted, and sex-adjusted models had ROC AUCs (95% CIs) of 0.9924 (0.9807-1), 0.9924 (0.9807-1), 0.9916 (0.9786-1), and 0.9950 (0.9861-1), respectively. Macimorelin performance was not meaningfully affected by age, BMI, or sex, indicating robustness for AGHD diagnosis. Of the 4 GH cutpoints evaluated, the cutpoint of 5.1 ng/mL provided maximal specificity (96%) and high sensitivity (92%) and was in good overall agreement with the ITT at the same cutpoint (87%).


Case Report: Interstitial-intralesional laser therapy and laser-assisted new attachment procedure for the treatment of alveolar bone loss provoked by an aggressive pyogenic granuloma.
Background: A pyogenic granuloma (PG) is a common benign vascular lesion found in the oral cavity. The gold standard treatment of this lesion, comprising surgical excision and the elimination of etiological factors, cannot avoid tooth loss in the case of an aggressive pyogenic granuloma. Because of the prominent properties of 980 nm and 635 nm diode lasers in photocoagulation and photobiomodulation, we applied these wavelengths in the treatment of a large pyogenic granuloma with alveolar bone loss. Case presentation: Our objective was to use a combination of interstitial-intralesional laser therapy, photocoagulation and laser-assisted new attachment procedure (LANAP) to preserve the teeth and periodontal tissue in a case of an aggressive pyogenic granuloma. Results: The patient was a 13-year-old Thai male with a pyogenic granuloma involving the interdental papilla and lingual gingiva of the lower left first and second molars. The teeth were also displaced by the lesion. After treatment with three sessions of photocoagulation, three sessions of interstitial-intralesional laser therapy and two sessions of LANAP, the lesion was completely resolved. The periodontal status of the teeth was improved at the six-month follow-up. Conclusion: The combination of interstitial-intralesional laser therapy, photocoagulation and LANAP was able to treat an aggressive pyogenic granuloma with tooth preservation.


Effect of osmotic ballast properties on the performance of a concentration gradient battery.
A concentration gradient battery (CGB) is an energy storage system comprised of a series of concentrated and dilute salt solution compartments, separated by ion exchange membranes (IEMs). The battery is charged by electrodialysis (ED), which increases the concentration gradient between these solutions, and discharged by reverse electrodialysis (RED), which allows these solutions to mix. In both ED and RED, water moves by osmosis from dilute to concentrated compartments, reducing the CGB faradaic and energy efficiency. A promising approach to mitigate osmosis is to use an osmotic ballast in the dilute solution to balance the osmotic pressure and reduce faradaic energy losses. The objective of this study was to investigate the impact of ballast properties (i.e., size, structure, end-group) on the faradaic and round-trip efficiency of the CGB. To accomplish this objective, we tested seven sugar and five glycol compounds as osmotic ballasts in a closed-loop cell. Results show that ballasts with high molecular weight generally resulted in higher faradaic efficiency and lower water transport compared with low molecular weight ballasts. Data also indicates that ballast with a cyclic structure (instead of linear), non-planar structure (instead of planar), and lower number of methyl end-groups led to lower water transport. Of all ballasts tested, sucrose performed best in terms of reducing non-ideal water transport (by 109%) and enhancing both faradaic and round-trip efficiencies (from 47.4% to 77.7% and 25.5% to 38.1%, respectively) compared with the non-ballasted CGB. Our results contribute to fundamental understanding of the impact of solute properties on water and small organic molecule transport in ion exchange membranes and indicate that ballasted CGBs can be further improved through development of optimized ballasts and selection of optimum membrane-ballast pairs. The improved understanding of ballast impact on CGB performance could be used for evaluation of potential ballast benefits in other membrane-based systems that may be impacted by osmosis such as the acid-base flow battery, waste heat recovery using RED, ED purification processes, osmotically assisted processes, and redox flow batteries.


The EFEMP1 gene: a frequent target for epigenetic silencing in multiple human pituitary adenoma subtypes.
In a genome-wide investigation we recently identified the EGF-containing fibulin-like extracellular matrix protein 1 gene, EFEMP1, as hypermethylated in growth hormone-secreting adenoma. In an independent cohort we determined expression of EFEMP1, CpG island methylation and histone tail modification status. The causal consequences of epigenetic modification were determined through epidrug-induced reversal and enforced EFEMP1 expression in GH3 cells. The majority of adenomas, irrespective of subtype, show reduced EFEMP1 expression. However, epigenetic change, as determined by CpG island methylation, was not invariantly associated with decreased EFEMP1 expression. Conversely, chromatin immunoprecipitation assays revealed enrichment for modifications associated with either active or silenced genes in adenoma that did or did not express EFEMP1 respectively. In AtT-20 and GH3 cells a causal relationship between epigenetic silencing and expression of EFEMP1 was established where co-incubation with the epidrugs zebularine and TSA induced expression of EFEMP1 and concomitant histone tail modifications toward those associated with expressed genes. Enforced expression of EFEMP1 in GH3 cells was without effect on cell proliferation or apoptotic end-points, however inhibition of endogenous matrix metalloproteinase (MMP)-2 expression was apparent. Primary adenomas did not show this relationship, however a positive correlation was apparent with the MMP7 transcript and perhaps reflects cell or species differences. The protein product of the EFEMP1 gene, fibulin-3, is reported to impact on multiple pathways in a cell-specific context. Subtype-independent loss of EFEMP1 expression in the majority of primary adenomas should prompt more detailed investigation in this tumour type.


Congenital macrothrombocytopenia with focal myelofibrosis due to mutations in human G6b-B is rescued in humanized mice.
Unlike primary myelofibrosis (PMF) in adults, myelofibrosis in children is rare. Congenital (inherited) forms of myelofibrosis (cMF) have been described, but the underlying genetic mechanisms remain elusive. Here we describe 4 families with autosomal recessive inherited macrothrombocytopenia with focal myelofibrosis due to germ line loss-of-function mutations in the megakaryocyte-specific immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptor G6b-B (G6b, C6orf25, or MPIG6B). Patients presented with a mild-to-moderate bleeding diathesis, macrothrombocytopenia, anemia, leukocytosis and atypical megakaryocytes associated with a distinctive, focal, perimegakaryocytic pattern of bone marrow fibrosis. In addition to identifying the responsible gene, the description of G6b-B as the mutated protein potentially implicates aberrant G6b-B megakaryocytic signaling and activation in the pathogenesis of myelofibrosis. Targeted insertion of human G6b in mice rescued the knockout phenotype and a copy number effect of human G6b-B expression was observed. Homozygous knockin mice expressed 25% of human G6b-B and exhibited a marginal reduction in platelet count and mild alterations in platelet function; these phenotypes were more severe in heterozygous mice that expressed only 12% of human G6b-B. This study establishes G6b-B as a critical regulator of platelet homeostasis in humans and mice. In addition, the humanized G6b mouse will provide an invaluable tool for further investigating the physiological functions of human G6b-B as well as testing the efficacy of drugs targeting this receptor.


DSM-IV and ICD-10 generalized anxiety disorder: discrepant diagnoses and associated disability.
It is commonly assumed that diagnoses according to DSM-IV and ICD-10 are equivalent. Recent discussions on generalized anxiety disorder (GAD) have suggested that ICD-10 criteria may be identifying a milder form of the disorder than DSM-IV. This report examines prevalence and associated disability of DSM-IV and ICD-10 GAD. The Composite International Diagnostic Interview was administered to a community sample of 10,641 people, and the diagnostic criteria that contributed to discrepancies between DSM-IV and ICD-10 GAD were identified. A multiple linear regression analysis was carried out to determine the strength of the relationship between disability, as measured by the SF-12, and discrepant diagnoses of GAD. The concordance between DSM-IV and ICD-10 GAD was fair (kappa = 0.39). The two sources of discrepancy when DSM-IV was positive and ICD-10 was negative resulted from the requirement in ICD-10 that the respondent endorse symptoms of autonomic arousal (ICD-10 criterion B) and the requirement that ICD-10 GAD does not co-occur with panic/agoraphobia, social phobia or obsessive-compulsive disorder (ICD-10 criterion C). The two major sources of discrepancy when ICD-10 was positive and DSM-IV was negative resulted from the requirement in DSM-IV that the worry be excessive (DSM-IV criterion A) and that it causes clinically significant distress or impairment (DSM-IV criterion E). DSM-only GAD cases had significantly higher levels of disability than ICD-only cases of GAD after controlling for demographic variables and the presence of comorbid psychiatric disorders. While the prevalence rates for DSM-IV and ICD-10 GAD are almost identical, these classification systems are diagnosing different groups of people.


Split liver transplantation (SLT).
In the last three decades liver transplantation (LT) has become a standard procedure for terminal liver failure. Anyway the procedure is highly limited by the availability of donor organs. The use of segmental liver grafts from living or cadaver donors are an attractive way to increase the donor pool for LT in adults and children. Between 1991 and April 1999 we performed 647 liver transplantations in 416 adults and 231 children. 431 OLT, 124 SLT and 92 LRLT. Commonly used segmental liver grafts are the full right graft, the full left graft, the left lateral lobe graft and the right extended graft from living or cadaver donors respectively. The 1-year survival of elective SLT in adults is 80.5% and in children 84.3% (SLT + LRLT). Splitting procedures in liver transplantation are a promising completion to whole organ transplantations. The results of split liver (SLT) and living related liver transplantations (LRLT) are comparable to whole organ transplantations. These methods are able to increase the organ pool and thus decrease the pretransplant mortality both in children and adults.


Inheritance of seed condensed tannins and their relationship with seed-coat color and pattern genes in common bean (Phaseolus vulgaris L.).
Condensed tannins are major flavonoid end products that affect the nutritional quality of many legume seeds. They chelate minerals and interact with proteins, thus reducing their bioavailability. Tannins also contribute to seed coat color and pigment distribution or intensity. The objective of this study was to analyze the relationship between quantitative trait loci (QTL) for seed tannin concentration in common bean and Mendelian genes for seed coat color and pattern. Three populations of recombinant inbred lines, derived from crosses between the Andean and Mesoamerican genepools were used for QTL identification and for mapping STS markers associated with seed color loci. Seed coat condensed tannins were determined with a butanol-HCl method and a total of 12 QTL were identified on separate linkage groups (LGs) in each of the populations with individual QTL explaining from 10 to 64% of the phenotypic variation for this trait. Loci on linkage groups B3 and B10 were associated with the Mendelian genes Z and Bip for partly colored seed coat pattern, while a QTL on linkage group B7 was associated with the P gene which is the primary locus for the control of color expression in beans. In conclusion, this study found that the inheritance of tannin concentration fits an oligogenic model and identifies novel putative alleles at seed coat color and pattern genes that control tannin accumulation. The results will be important for the genetic improvement of nutritionally enhanced or biofortified beans that have health promoting effects from higher polyphenolics or better iron bioavailability.


Citalopram versus other anti-depressive agents for depression.
Recent US and UK clinical practice guidelines recommend that second-generation antidepressants should be considered amongst the best first-line options when drug therapy is indicated for a depressive episode. Systematic reviews have already highlighted some differences in efficacy between second-generation antidepressants. Citalopram, one of the first selective serotonin reuptake inhibitors (SSRI) introduced in the market, is one of these antidepressant drugs that clinicians use for routine depression care. To assess the evidence for the efficacy, acceptability and tolerability of citalopram in comparison with tricyclics, heterocyclics, other SSRIs and other conventional and non-conventional antidepressants in the acute-phase treatment of major depression. We searched The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register and the Cochrane Central Register of Controlled Trials up to February 2012. No language restriction was applied. We contacted pharmaceutical companies and experts in this field for supplemental data. Randomised controlled trials allocating patients with major depression to citalopram versus any other antidepressants. Two reviewers independently extracted data. Information extracted included study characteristics, participant characteristics, intervention details and outcome measures in terms of efficacy (the number of patients who responded or remitted), patient acceptability (the number of patients who failed to complete the study) and tolerability (side-effects). Thirty-seven trials compared citalopram with other antidepressants (such as tricyclics, heterocyclics, SSRIs and other antidepressants, either conventional ones, such as mirtazapine, venlafaxine and reboxetine, or non-conventional, like hypericum). Citalopram was shown to be significantly less effective than escitalopram in achieving acute response (odds ratio (OR) 1.47, 95% confidence interval (CI) 1.08 to 2.02), but more effective than paroxetine (OR 0.65, 95% CI 0.44 to 0.96) and reboxetine (OR 0.63, 95% CI 0.43 to 0.91). Significantly fewer patients allocated to citalopram withdrew from trials due to adverse events compared with patients allocated to tricyclics (OR 0.54, 95% CI 0.38 to 0.78) and fewer patients allocated to citalopram reported at least one side effect than reboxetine or venlafaxine (OR 0.64, 95% CI 0.42 to 0.97 and OR 0.46, 95% CI 0.24 to 0.88, respectively). Some statistically significant differences between citalopram and other antidepressants for the acute phase treatment of major depression were found in terms of efficacy, tolerability and acceptability. Citalopram was more efficacious than paroxetine and reboxetine and more acceptable than tricyclics, reboxetine and venlafaxine, however, it seemed to be less efficacious than escitalopram. As with most systematic reviews in psychopharmacology, the potential for overestimation of treatment effect due to sponsorship bias and publication bias should be borne in mind when interpreting review findings. Economic analyses were not reported in the included studies, however, cost effectiveness information is needed in the field of antidepressant trials.


Activity-based photoacoustic probe for biopsy-free assessment of copper in murine models of Wilson's disease and liver metastasis.
The development of high-performance photoacoustic (PA) probes that can monitor disease biomarkers in deep tissue has the potential to replace invasive medical procedures such as a biopsy. However, such probes must be optimized for in vivo performance and exhibit an exceptional safety profile. In this study, we have developed PACu-1, a PA probe designed for biopsy-free assessment (BFA) of hepatic Cu via photoacoustic imaging. PACu-1 features a Cu(I)-responsive trigger appended to an aza-BODIPY dye platform that has been optimized for ratiometric sensing. Owing to its excellent performance, we were able to detect basal levels of Cu in healthy wild-type mice as well as elevated Cu in a Wilson's disease model and in a liver metastasis model. To showcase the potential impact of PACu-1 for BFA, we conducted two blind studies in which we were able to successfully identify Wilson's disease animals from healthy control mice in each instance.


Mutational analysis of the redox-sensitive transcriptional regulator OxyR: regions important for DNA binding and multimerization.
OxyR is a LysR-type transcriptional regulator which negatively regulates its own expression and positively regulates the expression of proteins important for the defense against hydrogen peroxide in Escherichia coli and Salmonella typhimurium. Using random mutagenesis, we isolated six nonrepressing OxyR mutants that were impaired in DNA binding. Five of the mutations causing the DNA binding defect mapped near the N-terminal helix-turn-helix motif conserved among the LysR family members, confirming that this region is a DNA binding domain in OxyR. The sixth nonrepressing mutant (with E-225 changed to K [E225K]) was found to be predominantly dimeric, in contrast to the tetrameric wild-type protein, suggesting that a C-terminal region defined by the E225K mutation is involved in multimerization.


Loss of three-dimensional canine mitral annular systolic contraction with reduced left ventricular volumes.
We have recently described an inhomogeneous pattern of systolic contraction of the mitral annulus (MA) in normovolemic dogs: the posterior annulus shortens, and the anterior annulus lengthens. MA dynamics, however, have not been studied in volume-depleted hearts. Eight radiopaque markers were placed equidistant from each other around the MA in seven dogs. As viewed from the left atrium, the segment between markers 1 and 2 (seg12) began at the posteromedial commissure, and remaining segments were numbered sequentially clockwise around the MA (ie, posterior MA encompassed seg12, seg23, seg34, and seg45; anterior MA encompassed seg56, seg67, seg78, and seg81). Marker images were obtained in sedated dogs by simultaneous biplane videofluoroscopy 7 to 12 days after marker implantation, and three-dimensional marker coordinates at end diastole (ED) and end systole (ES) were computed. Vena caval occlusion (VCO) was used to reduce left ventricular end-diastolic volume to 70 +/- 5% of baseline (BL). With VCO, mean MA area did not change from ED to ES (3.4 +/- 0.8 versus 3.6 +/- 0.7 cm2, P = NS) during the cardiac cycle. MA segmental systolic shortening values (negative values indicate lengthening) were as follows for BL and VCO, respectively (mean +/- SD): seg12, 7 +/- 9% and 0 +/- 13%; seg23, 8 +/- 10%* and 1 +/- 11%; seg34, 16 +/- 6%* and 4 +/- 9% seg45, 10 +/- 7%* and 2 +/- 13%; seg56, -4 +/- 5%* and -16 +/- 11%*; seg67, -7 +/- 7%* and -14 +/- 7%*; seg78, 3 +/- 2%* and -1 +/- 6%; and seg81, 6 +/- 5%* and -5 +/- 11% (*P < or = .05 versus zero changes, paired t test). With acute volume depletion, the five annular segments that shortened at BL no longer changed length; two anterior segments (seg56 and seg67) that lengthened at BL continued to lengthen significantly, and to a greater extent. These findings indicate that the anterior MA is a more dynamic structure than previously thought. Such dynamic motion may be important for normal mitral valvular function and possibly needs to be taken into account in the design of mitral valve reparative techniques.


Tunable terahertz wave generation through a bimodal laser diode and plasmonic photomixer.
We demonstrate a compact, robust, and stable terahertz source based on a novel two section digital distributed feedback laser diode and plasmonic photomixer. Terahertz wave generation is achieved through difference frequency generation by pumping the plasmonic photomixer with two output optical beams of the two section digital distributed feedback laser diode. The laser is designed to offer an adjustable terahertz frequency difference between the emitted wavelengths by varying the applied currents to the laser sections. The plasmonic photomixer is comprised of an ultrafast photoconductor with plasmonic contact electrodes integrated with a logarithmic spiral antenna. We demonstrate terahertz wave generation with 0.15-3 THz frequency tunability, 2 MHz linewidth, and less than 5 MHz frequency stability over 1 minute, at useful power levels for practical imaging and sensing applications.


Post-Translational Modifications of G Protein-Coupled Receptors Control Cellular Signaling Dynamics in Space and Time.
G protein-coupled receptors (GPCRs) are a large family comprising >800 signaling receptors that regulate numerous cellular and physiologic responses. GPCRs have been implicated in numerous diseases and represent the largest class of drug targets. Although advances in GPCR structure and pharmacology have improved drug discovery, the regulation of GPCR function by diverse post-translational modifications (PTMs) has received minimal attention. Over 200 PTMs are known to exist in mammalian cells, yet only a few have been reported for GPCRs. Early studies revealed phosphorylation as a major regulator of GPCR signaling, whereas later reports implicated a function for ubiquitination, glycosylation, and palmitoylation in GPCR biology. Although our knowledge of GPCR phosphorylation is extensive, our knowledge of the modifying enzymes, regulation, and function of other GPCR PTMs is limited. In this review we provide a comprehensive overview of GPCR post-translational modifications with a greater focus on new discoveries. We discuss the subcellular location and regulatory mechanisms that control post-translational modifications of GPCRs. The functional implications of newly discovered GPCR PTMs on receptor folding, biosynthesis, endocytic trafficking, dimerization, compartmentalized signaling, and biased signaling are also provided. Methods to detect and study GPCR PTMs as well as PTM crosstalk are further highlighted. Finally, we conclude with a discussion of the implications of GPCR PTMs in human disease and their importance for drug discovery. SIGNIFICANCE STATEMENT: Post-translational modification of G protein-coupled receptors (GPCRs) controls all aspects of receptor function; however, the detection and study of diverse types of GPCR modifications are limited. A thorough understanding of the role and mechanisms by which diverse post-translational modifications regulate GPCR signaling and trafficking is essential for understanding dysregulated mechanisms in disease and for improving and refining drug development for GPCRs.


Detection of restriction fragment length polymorphisms at the centromeres of human chromosomes by using chromosome-specific alpha satellite DNA probes: implications for development of centromere-based genetic linkage maps.
We describe a general strategy for the detection of high-frequency restriction fragment length polymorphisms in the centromeric regions of human chromosomes by molecular analysis of alpha satellite DNA, a diverse family of tandemly repeated DNA located near the centromeres of all human chromosomes. To illustrate this strategy, cloned alpha satellite repeats isolated from two human chromosomes, 17 and X, have been used under high-stringency conditions that take advantage of the chromosome-specific organization of this divergent repeated DNA family. Multiple high-frequency restriction fragment length polymorphisms are described for the centromeric region of both chromosome 17 and X chromosome. Mendelian inheritance of the variants is demonstrated. The X-linked alpha satellite polymorphisms in particular are highly informative and constitute a virtually unique centromeric DNA marker for each X chromosome examined. Since the strategy we describe is a general one, the alpha satellite family of DNA should provide a rich source of molecular variation in the human genome and should contribute to the development of centromere-based genetic linkage maps of human chromosomes.


Five-year experience with congenital cardiac surgery at National University Heart Centre, Singapore.
Surgical procedures performed for congenital heart disease are usually complex and variable. The aims of this paper were to analyse patient demographics in a centre that caters to congenital cardiac surgery, compare departmental standards to international centres, and investigate the relationship between patient volume and clinical outcome. A total of 163 patients who presented to the Cardiac, Thoracic and Vascular Surgery Department of the National University Hospital , Singapore between 2002 and 2006 were identified and studied retrospectively. Patient demographics were analysed. The mortality rates and patient volume were compared with those observed at international centres. The mean annual patient volume was 32.6 cases. The mean age of the patients was 15.7 years, with the oldest patient being 73 years old. 57.1 percent of the patients were Chinese, 23.3 percent were Malay and 19.6 percent were Indian and other races. Foreigners made up nearly half of the patient cohort (45.4 percent). Atrial septal defect was found to be the most common diagnosis (n is 64), with the secundum being most commonly involved (76.9 percent). The commonest postoperative morbidities encountered were arrhythmias and pleural effusions. Patient volume was not found to be a significant factor affecting clinical outcomes. With a growing population of adults with congenital heart disease and a significant number of foreign patients, improvements to our resources and infrastructure need to be considered in order to cope with the increasing demands. Despite having a low patient volume, the centre is still able to provide congenital heart surgery with good clinical outcomes that are comparable to those of international centres with similar or higher patient volumes.


Examining the meaning attached to mental illness and mental health services among justice system-involved youth and their parents.
A large percentage of youth involved in the juvenile justice system experience mental health problems, yet many do not receive mental health care. In this study, we used a process-focused framework of mental health decision making to gain insight into the use of mental health services among these youth. In-depth interviews were conducted with nine youth and nine parents participating in a program servicing youth with mental health problems who have been in detention. Themes related to problem recognition, the decision to seek and participate in services, subjective norms, and juvenile justice system involvement emerged. Most families acknowledged their youth was having problems, but few defined those problems in mental health terms. This did not prevent them from seeking services, although some were not able to access adequate services until the justice system became involved. Participants were aware of negative attitudes about mental illness, and might have limited their social networks to shield themselves.


Movement pattern training compared with standard strengthening and flexibility among patients with hip-related groin pain: results of a pilot multicentre randomised clinical trial.
Pilot, multicentre randomised clinical trial (RCT). Assess viability of performing a definitive RCT and compare preliminary effects of movement pattern training (MoveTrain) and strengthening/flexibility (Standard) to improve function in people with chronic hip-related groin pain (HRGP). To determine the best physical therapist-led intervention for patients with HRGP, we must understand treatment effects of different treatment modes. Forty-six patients (17M:29F; 29±5.3 years; body mass index 25.6±6.3 kg/m2) with HRGP were randomised. MoveTrain included task-specific training to optimise biomechanics during daily tasks. Standard included strengthening/flexibility. Treatment included 10 visits/12 weeks and home exercise programme (HEP). Primary outcomes for feasibility were recruitment, retention, treatment adherence and treatment fidelity. Secondary outcomes were patient-reported function (Hip disability and Osteoarthritis Outcome Score (HOOS)), lower extremity kinematics and hip muscle strength. We achieved target recruitment, and retention was excellent (91%). Patient session attendance was high (93%); however, reported HEP adherence (62%) was lower than expected. Physical therapists' adherence to treatment protocols was high (90%). Patients demonstrated high treatment receipt; 91% of exercises performed were rated independent. Both groups demonstrated clinically important improvements in function (HOOS) and muscle strength; however, there were no between-group differences (HOOS subscales, p≥0.13, strength, p≥0.34). Compared with Standard, MoveTrain demonstrated greater reductions in hip adduction (p=0.016) and pelvic drop (p=0.026) during a single leg squat. No adverse events were noted. Our experience in completing this RCT confirmed that a larger, multicentre RCT is feasible and highlighted modifications we will implement to optimise the future RCT. NCT02913222.


Therapeutic Outcomes in AIDS-Associated Kaposi's Sarcoma Patients on Antiretroviral Therapy Treated with Chemotherapy at Two Tertiary Hospitals in Lusaka, Zambia.
The incidence of HIV-associated Kaposi's sarcoma (KS) remains high in Zambia in the antiretroviral therapy era. The most efficacious treatment regimen for KS has yet to be established. In both developed and developing countries, treatment regimens have had limited efficacy. Late presentation in Africa affects therapeutic outcomes. The aim of this study was to determine therapeutic outcomes of epidemic KS patients on combination antiretroviral therapy (cART) after completion of six cycles of Adriamycin, Bleomycin, and Vincristine (ABV) chemotherapy. This was a descriptive cross-sectional study. Study participants were drawn from a study database of confirmed incident KS patients seen at the Skin Clinic of the University Teaching Hospitals (UTH) during the period between August, 2015 and September, 2016. Of the 38 successfully recruited study participants, a complete response was documented in 18 (47%) after 6 cycles of ABV whereas 20 (53%) experienced a partial response. KS recurrence was observed in 8 (44%) of the individuals that experienced an initial complete response. At the time of the study, clinical assessment revealed that KS lesions had completely regressed in 21 (55%) of all the patients. ABV chemotherapy appears ineffective in long-term resolution of epidemic KS patients on ART. Recurrence rates are high after chemotherapy in patients that experience initially favorable responses to treatment. There is a need to diagnose KS earlier, and to develop more efficacious treatment options in order to reduce recurrence rates for epidemic KS.


Comparing type of health insurance among low-income children: a mixed-methods study from Oregon.
We employed a mixed-methods study of primary data from a statewide household survey and in-person interviews with parents to examine-quantitatively and qualitatively-whether low-income children experienced differences between public and private insurance coverage types. We carried out 24 in-depth interviews with a subsample of respondents to Oregon's 2005 Children's Access to Healthcare Study (CAHS), analyzed using a standard iterative process and immersion/crystallization cycles. Qualitative findings guided quantitative analyses of CAHS data that assessed associations between insurance type and parental-reported unmet children's health care needs. Interviewees uniformly reported that stable health insurance was important, but there was no consensus regarding which type was superior. Quantitatively, there were only a few significant differences. Cross-sectionally, compared with private coverage, public coverage was associated with higher odds of unmet specialty care needs (odds ratio [OR] 3.54; 95% confidence interval [CI] 1.52-8.24). Comparing full-year coverage patterns, those with public coverage had lower odds of unmet prescription needs (OR 0.60, 95% CI 0.36-0.99) and unmet mental health counseling needs (OR 0.24, 95% CI 0.10-0.63), compared with privately covered children. Low-income Oregon parents reported few differences in their child's experience with private versus public coverage.


Patient ability and willingness to participate in a web-based intervention to improve hypertension control.
Patient-shared electronic health records provide opportunities for care outside of office visits. However, those who might benefit may be unable to or choose not to use these resources, while others might not need them. Electronic Communications and Home Blood Pressure Monitoring (e-BP) was a randomized trial that demonstrated that Web-based pharmacist care led to improved blood pressure (BP) control. During recruitment we attempted to contact all patients with hypertension from 10 clinics to determine whether they were eligible and willing to participate. We wanted to know whether particular subgroups, particularly those from vulnerable populations, were less willing to participate or unable to because they lacked computer access. From 2005 to 2006, we sent invitation letters to and attempted to recruit 9298 patients with hypertension. Eligibility to participate in the trial included access to a computer and the Internet, an email address, and uncontrolled BP (BP ≥ 140/90 mmHg). Generalized linear models within a modified Poisson regression framework were used to estimate the relative risk (RR) of ineligibility due to lack of computer access and of having uncontrolled BP. We were able to contact 95.1% (8840/9298) of patients. Those refusing participation (3032/8840, 34.3%) were significantly more likely (P < .05) to be female, be nonwhite, have lower levels of education, and have Medicaid insurance. Among patients who answered survey questions, 22.8% (1673/7354) did not have computer access. Older age, minority race, and lower levels of education were risk factors for lack of computer access, with education as the strongest predictor (RR 2.63, 95% CI 2.30-3.01 for those with a high school degree compared to a college education). Among hypertensive patients with computer access who were willing to participate, African American race (RR 1.22, 95% CI 1.06-1.40), male sex (RR 1.28, 95% CI 1.18-1.38), and obesity (RR 1.53, 95% CI 1.31-1.79) were risk factors for uncontrolled BP. Older age, lower socioeconomic status, and lower levels of education were associated with decreased access to and willingness to participate in a Web-based intervention to improve hypertension control. Failure to ameliorate this may worsen health care disparities. Clinicaltrials.gov NCT00158639; http://www.clinicaltrials.gov/ct2/show/NCT00158639 (Archived by WebCite at http://www.webcitation.org/5v1jnHaeo).


The effect of opinion clustering on disease outbreaks.
Many high-income countries currently experience large outbreaks of vaccine-preventable diseases such as measles despite the availability of highly effective vaccines. This phenomenon lacks an explanation in countries where vaccination rates are rising on an already high level. Here, we build on the growing evidence that belief systems, rather than access to vaccines, are the primary barrier to vaccination in high-income countries, and show how a simple opinion formation process can lead to clusters of unvaccinated individuals, leading to a dramatic increase in disease outbreak probability. In particular, the effect of clustering on outbreak probabilities is strongest when the vaccination coverage is close to the level required to provide herd immunity under the assumption of random mixing. Our results based on computer simulations suggest that the current estimates of vaccination coverage necessary to avoid outbreaks of vaccine-preventable diseases might be too low.


Chaotic Structure of Oil Prices, Inflation and Unemployment.
This article investigates the chaotic relationship among inflation rate, unemployment rate and oil prices over the period of January, 1974-October, 2018 in the USA. This study complements the previous studies on this subject. However, it differs from the existing literature in examination of inflation-unemployment trade-off by a neural network model in which oil prices are considered as an exogenous variable, and in analyzing the chaotic causality relation among the variables by Hristu-Varsakelis and Kyrtsou and Bai nonlinear causality tests. The results first suggested by a class of neural network model, which was the multi-layer perceptron (MLP), pointed out an important relation among the analyzed variables. Accordingly, oil price changes have substantial effect on unemployment and inflation. Following, the empirical findings of Hristu-Varsakelis and Kyrtsou and Bai nonlinear causality tests show that there is a unidirectional chaotic relation from oil price to inflation, from oil price to unemployment and from inflation to unemployment.


Role of clinically indicated transbronchial lung biopsies in the management of pediatric post-lung transplant patients.
Although transbronchial biopsy (TBB) is the definitive method for diagnosing graft dysfunction after pediatric lung transplantation, concern over procedural complications has limited its use. We reviewed our institutional experience with clinically indicated TBB to determine its safety and efficacy with emphasis on how biopsy findings altered management. A retrospective chart review was done of 61 pediatric lung transplantation patients undergoing 179 TBB procedures. Data were collected on pre-TBB symptoms, pulmonary function testing, and imaging studies. The prebiopsy diagnosis was noted and compared with the findings from TBB to see how frequently treatment changed after biopsy. Age at TBB ranged from 2 months to 20 years, with an average of 3 biopsies per patient. There was no procedure-related mortality. The incidence of complications was 9% and included important bleeding with spontaneous resolution in 6% and pneumothorax in 3%. The usual indication for TBB was a change in the chest roentgenogram, frequently accompanied by a decrease in flows on spirometry. The TBB specimens were adequate for pathologic analysis 92% of the time, and a specific pathologic diagnosis could be made in 54% of cases. The findings from TBB altered the clinical management of the patient 64% of the time. In pediatric lung transplant recipients presenting with graft dysfunction, TBB is a low-risk diagnostic procedure that yields clinically useful information in a majority of cases. In our experience, the findings from TBB altered medical treatment in 64% of patients. Treatment was most often changed in the group diagnosed with rejection as the probable cause of graft dysfunction.


Aging induced loss of complexity and dedifferentiation: consequences for coordination dynamics within and between brain, muscular and behavioral levels.
Growing evidence demonstrates that aging not only leads to structural and functional alterations of individual components of the neuro-musculo-skeletal system (NMSS) but also results in a systemic re-organization of interactions within and between the different levels and functional domains. Understanding the principles that drive the dynamics of these re-organizations is an important challenge for aging research. The present Hypothesis and Theory paper is a contribution in this direction. We propose that age-related declines in brain and behavior that have been characterized in the literature as dedifferentiation and the loss of complexity (LOC) are: (i) synonymous; and (ii) integrated. We argue that a causal link between the aforementioned phenomena exists, evident in the dynamic changes occurring in the aging NMSS. Through models and methods provided by a dynamical systems approach to coordination processes in complex living systems, we: (i) formalize operational hypotheses about the general principles of changes in cross-level and cross-domain interactions during aging; and (ii) develop a theory of the aging NMSS based on the combination of the frameworks of coordination dynamics (CD), dedifferentiation, and LOC. Finally, we provide operational predictions in the study of aging at neural, muscular, and behavioral levels, which lead to testable hypotheses and an experimental agenda to explore the link between CD, LOC and dedifferentiation within and between these different levels.


Parental country of birth is a major determinant of childhood type 1 diabetes in Sweden.
To test the hypothesis that the risk of childhood diabetes type 1 increases with migration from a low to a high incidence region. Register study of a national cohort of 783 547 children born between 1987 and 1993 who remained in Sweden in 2002, including 3225 children with childhood type 1 diabetes identified in hospital discharge data. Logistic regression analysis was used to test the hypotheses. Offspring of two parents born in very low (Asia excluding Middle East and Latin America) and low (southern and eastern Europe and the Middle East) incidence regions had the lowest adjusted odds ratios (ORs) of childhood type 1 diabetes; 0.21 (0.11-0.41) and 0.37 (0.29-0.48), respectively, compared with the Swedish majority population. When one parent was born in a low incidence country and one parent was Swedish born, the adjusted ORs increased but remained lower than the Swedish majority population. Parental country of birth is an important determinant of childhood type 1 in Sweden. Heritable factors seem most likely to explain this pattern.


Molecular characterization of novel sulfotransferases from the tick, Ixodes scapularis.
Ixodes scapularis, commonly known as the blacklegged or deer tick, is the main vector of Lyme disease in the United States. Recent progress in transcriptome research has uncovered hundreds of different proteins expressed in the salivary glands of hard ticks, the majority of which have no known function, and include many novel protein families. We recently identified transcripts coding for two putative cytosolic sulfotransferases in these ticks which recognized phenolic monoamines as their substrates. In this current study, we characterize the genetic expression of these two cytosolic sulfotransferases throughout the tick life cycle as well as the enzymatic properties of the corresponding recombinant proteins. Interestingly, the resultant recombinant proteins showed sulfotransferase activity against both neurotransmitters dopamine and octopamine. The two sulfotransferase genes were coded as Ixosc SULT 1 & 2 and corresponding proteins were referred as Ixosc Sult 1 and 2. Using gene-specific primers, the sulfotransferase transcripts were detected throughout the blacklegged tick life cycle, including eggs, larvae, nymphs, adult salivary glands and adult midgut. Notably, the mRNA and protein levels were altered upon feeding during both the larval and nymphal life stages. Quantitative PCR results confirm that Ixosc SULT1 was statistically increased upon blood feeding while Ixosc SULT 2 was decreased. This altered expression led us to further characterize the function of these proteins in the Ixodid tick. The sulfotransferase genes were cloned and expressed in a bacterial expression system, and purified recombinant proteins Ixosc Sult 1(R) and 2(R) showed sulfotransferase activity against neurotransmitters dopamine and octopamine as well as the common sulfotransferase substrate p-nitrophenol. Thus, dopamine- or octopamine-sulfonation may be involved in altering the biological signal for salivary secretion in I. scapularis. Collectively, these results suggest that a function of Ixosc Sult 1 and Sult 2 in Ixodid tick salivary glands may include inactivation of the salivation signal via sulfonation of dopamine or octopamine.


Prognostic factors and course for successful clinical outcome quality of life and patients' perceived effect after a cognitive behavior therapy for chronic non-specific low back pain: A 12-months prospective study.
This study investigates the clinical course of and prognostic factors for quality of life (Short Form 36 items Health survey (SF-36)) and global perceived effect (GPE) in patients treated for chronic non-specific low back pain at 5 and 12-months follow-up. Data from a prospective cohort (n = 1760) of a rehabilitation center were used, where patients followed a 2-months cognitive behavior treatment. The outcome 'improvement in quality of life (SF-36)' was defined as a 10% increase in score on the SF-36 at follow-up compared with baseline. On the GPE scale, patients who indicated to be 'much improved' were coded as 'clinically improved'. Multivariable logistic regression analysis included 23 baseline characteristics. At 5-months follow-up, scores on the SF-36 Mental Component Scale (SF-36; MCS) and the Physical Component Scale (SF-36; PCS) had increased from 46.6 (SD 10.3) to 50.4 (SD 9.8) and from 31.9 (SD 7.1) to 46.6 (SD 10.3), respectively. At 5-months follow-up, 53.0% of the patients reported clinical improvement (GPE) which increased to 60.3% at 12-months follow-up. The 10% improvement in quality of life (SF-36 MCS) at 5-months follow-up was associated with patient characteristics and psychological factors. At 5-months follow-up, the 10% improvement in quality of life (SF-36 PCS) and GPE was associated with patient characteristics, physical examination, work-related factors and psychological factors; for GPE, an association was also found with clinical status. At 12-months follow-up GPE was associated with patient characteristics, clinical status, physical examination and work-related factors. The next phase in this prognostic research is external validation of these results.


Comparison of ferromagnetic induction and bipolar electrosurgery and suction in corticotomies in pig cerebrum.
The effects of newer energy-based surgical dissection and coagulation modalities on cerebral tissue have not been investigated. Several instruments have been developed to address the limitations of traditional electrosurgical instruments in the nervous system. We compared the effects of standard bipolar electrocautery and suction (BPS) with those of a new ferromagnetic induction (FMI) device in corticotomies of pig cerebral tissue as assessed by magnetic resonance imaging (MRI) and histological analysis. Three adult pigs underwent bilateral corticotomies (3 cm long×1 cm deep) using both FMI and BPS. The acute cerebral tissue edema created by each method was measured on coronal volumetric T2-weighted MRI sequences immediately after surgery. A lateral thermal "damage index" was calculated by dividing the width of the visible T2 tissue edema by the measured depth. The radiographic damage indices with each method were compared statistically. Histological analysis of each incision was conducted to compare the extent of tissue damage. MRI showed that the mean radiographic damage index of each corticotomy was significantly lower with the FMI (0.30 ± 0.02 (0.28-0.32)) than with the BPS method (0.54 ± 0.11 (0.42-0.64)) (p = 0.02). Histological analysis suggested a correlation with the radiographic findings as the FMI tissue samples demonstrated less adjacent tissue damage than BPS. FMI appeared to cause less adjacent tissue damage than the BPS method in pig cerebral tissue based on quantitative radiographic and qualitative histological analysis. Future studies are needed to investigate the clinical implications of energy-based surgical dissection on cerebral tissue.


Analysis of the validity of the mathematical assumptions of electrical impedance tomography for human head tissues.
Objective:To determine the validity of the key mathematical assumptions used in electrical impedance tomography for human head tissues.Approach:Conductivity and permittivity data collected from available literature for each tissue within the human head have been evaluated and critiqued. The most relevant dielectric tissue data for each tissue was then used to assess the validity of the mathematical assumptions of electrical impedance tomography in terms of their suitability for human head imaging in order to estimate related errors.Main Results:For induced currents with frequencies greater than 200 Hz the internal current source density is negligible. The assumption that magnetic effects are negligible is valid to an error of 1.7% for human head tissues for frequencies below 1 MHz. The capacitive effects are negligible for CSF, dura mater, blood, bone (cortical), and deep tissue skin for frequencies less than 3.2 MHz, 320 kHz, 25 kHz, 3.2 kHz, and 130 Hz respectively. However, the capacitive effects are not negligible for brain tissues, as the minimum error for brain tissues across the frequency range of 10 Hz to 100 GHz is 6.2% at 800 Hz, and the maximum error is 410% at 20 GHz.Significance:It is often assumed that the mathematical reduction of the base equations is valid for human head tissues over a broad frequency range; this study shows that these assumptions are not true for all tissues at all frequencies. False assumptions will result in greater errors and local distortions within tomographic images of the human head using electrical impedance tomography. This study provides the relationships between injected current frequency and the validity of the mathematical assumptions for each individual tissue, providing greater awareness of the magnitude of possible distortions.


Residential mobility among foreign-born persons living in Sweden is associated with lower mortality.
There have been few longitudinal studies on the effect of within-country mobility on patterns of mortality in deceased foreign-born individuals. The results have varied; some studies have found that individuals who move around within the same country have better health status than those who do not change their place of residence. Other studies have shown that changing one's place of residence leads to more self-reported health problems and diseases. Our aim was to analyze the pattern of mortality in deceased foreign-born persons living in Sweden during the years 1970-1999 in relation to distance mobility. Data from Statistics Sweden and the National Board of Health and Welfare was used, and the study population consisted of 281,412 foreign-born persons aged 16 years and over who were registered as living in Sweden in 1970. Distance mobility did not have a negative effect on health. Total mortality was lower (OR 0.71; 95% CI 0.69-0.73) in foreign-born persons in Sweden who had changed their county of residence during the period 1970-1990. Higher death rates were observed, after adjustment for age, in three ICD diagnosis groups "Injury and poisoning", "External causes of injury and poisoning", and "Diseases of the digestive system" among persons who had changed county of residence.


The efficacy of low and moderate dosage of diazepam on sleep bruxism in children: A randomized placebo-controlled clinical trial.
Sleep bruxism (SB) in children is commonly a self-limited problem; however, therapy of the condition may be needed to improve sleep quality of parents and children. Benzodiazepines have some success in controlling adult bruxism. The objective of this study was to evaluate the effect and the safety of a short course of diazepam on controlling SB in healthy children. In this double-blind, randomized placebo-controlled clinical trial, 109 children with SB were randomly assigned to three groups, receiving low or moderate dose of diazepam or placebo for 2 weeks. For children aged 2-8 years, the dose of 2.5 and 5 mg was considered as low and moderate dose consequently. In children >8 years, the doses were doubled. The severity of SB was evaluated at the beginning and also 2, 8, and 12 weeks thereafter. Data were collected by a questionnaire completed by parents including frequency of SB per week and per night and duration of each SB, as bruxism severity score (BSS). A mixed-model ANOVA was used to assess the differences of mean BSS between different groups and measurement times. From 109 children recruited, 90 completed the study. After 2 weeks of intervention, the mean BSS decreased significantly in all groups (P = 0.0001), but it was not significantly different between groups in any of follow-ups (P = 0.554). Next-day sleepiness was assessed at week 2 of the study and was significantly higher in the groups using diazepam (P = 0.026). Short course of diazepam was not more effective than placebo for long-term control of SB in children.


Roadmap for naming uncultivated Archaea and Bacteria.
The assembly of single-amplified genomes (SAGs) and metagenome-assembled genomes (MAGs) has led to a surge in genome-based discoveries of members affiliated with Archaea and Bacteria, bringing with it a need to develop guidelines for nomenclature of uncultivated microorganisms. The International Code of Nomenclature of Prokaryotes (ICNP) only recognizes cultures as 'type material', thereby preventing the naming of uncultivated organisms. In this Consensus Statement, we propose two potential paths to solve this nomenclatural conundrum. One option is the adoption of previously proposed modifications to the ICNP to recognize DNA sequences as acceptable type material; the other option creates a nomenclatural code for uncultivated Archaea and Bacteria that could eventually be merged with the ICNP in the future. Regardless of the path taken, we believe that action is needed now within the scientific community to develop consistent rules for nomenclature of uncultivated taxa in order to provide clarity and stability, and to effectively communicate microbial diversity.


Identification of genes differentially regulated by glucocorticoids and progestins using a Cre/loxP-mediated retroviral promoter-trapping strategy.
Glucocorticoids and progestins are two classes of steroid hormone with very distinct biological functions. However, the glucocorticoid receptor (GR) and the progesterone receptor (PR) share many structural and functional similarities. One way that glucocorticoids and progestins can exert different biological effects is through their different abilities to regulate the expression of certain target genes. A strategy employing a retroviral promoter-trap and Cre/loxP-mediated site-specific recombination has been developed to identify genes that are differentially regulated by glucocorticoids and progestins. A mouse fibroblast cell line (4F) stably expressing both GR and PR and containing a single copy of a multifunctional selection plasmid is generated. This line is transduced with a self-inactivating retroviral promoter-trap vector carrying coding sequences for Cre-recombinase (Cre) in the U3 region. Integration of the provirus places Cre expression under the control of a genomic flanking sequence. Activation of Cre expression from integration into active genes results in a permanent switch between the selectable marker genes that converts the cells from neomycin-resistant to hygromycin-resistant. Selection for hygromycin resistance after hormone treatment yields recombinants in which Cre sequences in the U3 region are expressed from hormone-inducible upstream cellular promoters. Because Cre-mediated recombination is a permanent event, the expression of the selectable marker genes is independent of ongoing Cre expression. Thus this system permits the identification of genes that are transiently or weakly induced by hormone.


Toward Worldwide Hepcidin Assay Harmonization: Identification of a Commutable Secondary Reference Material.
Absolute plasma hepcidin concentrations measured by various procedures differ substantially, complicating interpretation of results and rendering reference intervals method dependent. We investigated the degree of equivalence achievable by harmonization and the identification of a commutable secondary reference material to accomplish this goal. We applied technical procedures to achieve harmonization developed by the Consortium for Harmonization of Clinical Laboratory Results. Eleven plasma hepcidin measurement procedures (5 mass spectrometry based and 6 immunochemical based) quantified native individual plasma samples (n = 32) and native plasma pools (n = 8) to assess analytical performance and current and achievable equivalence. In addition, 8 types of candidate reference materials (3 concentrations each, n = 24) were assessed for their suitability, most notably in terms of commutability, to serve as secondary reference material. Absolute hepcidin values and reproducibility (intrameasurement procedure CVs 2.9%-8.7%) differed substantially between measurement procedures, but all were linear and correlated well. The current equivalence (intermeasurement procedure CV 28.6%) between the methods was mainly attributable to differences in calibration and could thus be improved by harmonization with a common calibrator. Linear regression analysis and standardized residuals showed that a candidate reference material consisting of native lyophilized plasma with cryolyoprotectant was commutable for all measurement procedures. Mathematically simulated harmonization with this calibrator resulted in a maximum achievable equivalence of 7.7%. The secondary reference material identified in this study has the potential to substantially improve equivalence between hepcidin measurement procedures and contributes to the establishment of a traceability chain that will ultimately allow standardization of hepcidin measurement results.


Catalytic mechanism revealed by the crystal structure of undecaprenyl pyrophosphate synthase in complex with sulfate, magnesium, and triton.
Undecaprenyl pyrophosphate synthase (UPPs) catalyzes chain elongation of farnesyl pyrophosphate (FPP) to undecaprenyl pyrophosphate (UPP) via condensation with eight isopentenyl pyrophosphates (IPP). UPPs from Escherichia coli is a dimer, and each subunit consists of 253 amino acid residues. The chain length of the product is modulated by a hydrophobic active site tunnel. In this paper, the crystal structure of E. coli UPPs was refined to 1.73 A resolution, which showed bound sulfate and magnesium ions as well as Triton X-100 molecules. The amino acid residues 72-82, which encompass an essential catalytic loop not seen in the previous apoenzyme structure (Ko, T.-P., Chen, Y. K., Robinson, H., Tsai, P. C., Gao, Y.-G., Chen, A. P.-C., Wang, A. H.-J., and Liang, P.-H. (2001) J. Biol. Chem. 276, 47474-47482), also became visible in one subunit. The sulfate ions suggest locations of the pyrophosphate groups of FPP and IPP in the active site. The Mg2+ is chelated by His-199 and Glu-213 from different subunits and possibly plays a structural rather than catalytic role. However, the metal ion is near the IPP-binding site, and double mutation of His-199 and Glu-213 to alanines showed a remarkable increase of Km value for IPP. Inside the tunnel, one Triton surrounds the top portion of the tunnel, and the other occupies the bottom part. These two Triton molecules may mimic the hydrocarbon moiety of the UPP product in the active site. Kinetic analysis indicated that a high concentration (>1%) of Triton inhibits the enzyme activity.


The evolution of chloroplast genome structure in ferns.
The plastid genome (plastome) is a rich source of phylogenetic and other comparative data in plants. Most land plants possess a plastome of similar structure. However, in a major group of plants, the ferns, a unique plastome structure has evolved. The gene order in ferns has been explained by a series of genomic inversions relative to the plastome organization of seed plants. Here, we examine for the first time the structure of the plastome across fern phylogeny. We used a PCR-based strategy to map and partially sequence plastomes. We found that a pair of partially overlapping inversions in the region of the inverted repeat occurred in the common ancestor of most ferns. However, the ancestral (seed plant) structure is still found in early diverging branches leading to the osmundoid and filmy fern lineages. We found that a second pair of overlapping inversions occurred on a branch leading to the core leptosporangiates. We also found that the unique placement of the gene matK in ferns (lacking a flanking intron) is not a result of a large-scale inversion, as previously thought. This is because the intron loss maps to an earlier point on the phylogeny than the nearby inversion. We speculate on why inversions may occur in pairs and what this may mean for the dynamics of plastome evolution.


Removal of phthalates and pharmaceuticals from municipal wastewater by graphene adsorption process.
In this work graphene was used for evaluation of its adsorption behavior and performance in removing phthalate esters and pharmaceuticals in municipal wastewater. Di-n-butyl phthalate (DnBP), di-(2-ethylhexyl) phthalate (DEHP), acetaminophen (ACE), caffeine (CAF), cephalexin (CLX), and sulfamethoxazole (SMX) were emerging contaminants (ECs) with detection frequencies over 92% in a one-year monitoring of the occurrence of ECs in influent samples of a sewage treatment plant in Taiwan. Thus, these ECs were selected as the target contaminants for removal by graphene adsorption process. Experimental results showed that the adsorption isotherm data were fitted well to Langmuir model equation. It was also found that the adsorption process obeyed the pseudo-second-order kinetics. A graphene dosage of 0.1 g/L and adsorption time of 12 h were found to be the optimal operating conditions for the ECs of concern in model solutions in a preliminary study. By using the determined optimal operating conditions for removal of such ECs in actual municipal wastewater, removal efficiencies for various ECs were obtained and given as follows: (1) DnBP, 89%, (2) DEHP, 86%, (3) ACE, 43%, (4) CAF, 84%, (5) CLX, 81%, and (6) SMX, 34%.


Laryngeal muscle activities during progressive hypercapnia and hypoxia in awake and sleeping dogs.
Laryngeal, intercostal and diaphragmatic muscle activities were recorded during progressive hypercapnia and hypoxia in dogs with chronically implanted electrodes. As ventilation increased during progressive chemoreceptor stimulation, inspiratory activity of the posterior cricoarytenoid muscle, a laryngeal abductor, and of the cricothyroid muscle were augmented. When expiratory flow rates reached 2-3 times resting levels, both of these muscles were also active during expiration and recruitment of the internal intercostal muscles was observed. The thyroarytenoid muscle, a laryngeal adductor, was active only rarely and no consistent activation of this muscle was observed with either hypercapnia or hypoxia. The patterns of muscle activation in response to respiratory stimulation were not different during wakefulness, slow wave sleep, and rapid eye movement sleep. The results indicate that the laryngeal muscles are activated during hypercapnia and hypoxia in a manner which reduces both inspiratory and expiratory airflow resistance regardless of sleep-wakefulness state.


Deconstructing multisensory enhancement in detection.
The mechanisms responsible for the integration of sensory information from different modalities have become a topic of intense interest in psychophysics and neuroscience. Many authors now claim that early, sensory-based cross-modal convergence improves performance in detection tasks. An important strand of supporting evidence for this claim is based on statistical models such as the Pythagorean model or the probabilistic summation model. These models establish statistical benchmarks representing the best predicted performance under the assumption that there are no interactions between the two sensory paths. Following this logic, when observed detection performances surpass the predictions of these models, it is often inferred that such improvement indicates cross-modal convergence. We present a theoretical analyses scrutinizing some of these models and the statistical criteria most frequently used to infer early cross-modal interactions during detection tasks. Our current analysis shows how some common misinterpretations of these models lead to their inadequate use and, in turn, to contradictory results and misleading conclusions. To further illustrate the latter point, we introduce a model that accounts for detection performances in multimodal detection tasks but for which surpassing of the Pythagorean or probabilistic summation benchmark can be explained without resorting to early cross-modal interactions. Finally, we report three experiments that put our theoretical interpretation to the test and further propose how to adequately measure multimodal interactions in audiotactile detection tasks.


Stabilization wedges: solving the climate problem for the next 50 years with current technologies.
Humanity already possesses the fundamental scientific, technical, and industrial know-how to solve the carbon and climate problem for the next half-century. A portfolio of technologies now exists to meet the world's energy needs over the next 50 years and limit atmospheric CO2 to a trajectory that avoids a doubling of the preindustrial concentration. Every element in this portfolio has passed beyond the laboratory bench and demonstration project; many are already implemented somewhere at full industrial scale. Although no element is a credible candidate for doing the entire job (or even half the job) by itself, the portfolio as a whole is large enough that not every element has to be used.


Appetite Control across the Lifecourse: The Acute Impact of Breakfast Drink Quantity and Protein Content. The Full4Health Project.
Understanding the mechanisms of hunger, satiety and how nutrients affect appetite control is important for successful weight management across the lifecourse. The primary aim of this study was to describe acute appetite control across the lifecourse, comparing age groups (children, adolescents, adults, elderly), weight categories, genders and European sites (Scotland and Greece). Participants (n = 391) consumed four test drinks, varying in composition (15% (normal protein, NP) and 30% (high protein, HP) of energy from protein) and quantity (based on 100% basal metabolic rate (BMR) and 140% BMR), on four separate days in a double-blind randomized controlled study. Ad libitum energy intake (EI), subjective appetite and biomarkers of appetite and metabolism (adults and elderly only) were measured. The adults' appetite was significantly greater than that of the elderly across all drink types (p < 0.004) and in response to drink quantities (p < 0.001). There were no significant differences in EI between age groups, weight categories, genders or sites. Concentrations of glucagon-like peptide 1 (GLP-1) and peptide YY (PYY) were significantly greater in the elderly than the adults (p < 0.001). Ghrelin and fasting leptin concentrations differed significantly between weight categories, genders and sites (p < 0.05), while GLP-1 and PYY concentrations differed significantly between genders only (p < 0.05). Compared to NP drinks, HP drinks significantly increased postprandial GLP-1 and PYY (p < 0.001). Advanced age was concomitant with reduced appetite and elevated anorectic hormone release, which may contribute to the development of malnutrition. In addition, appetite hormone concentrations differed between weight categories, genders and geographical locations.