Factors influencing QTL mapping accuracy under complicated genetic models by computer simulation.
The accuracy of quantitative trait loci (QTLs) identified using different sample sizes and marker densities was evaluated in different genetic models. Model I assumed one additive QTL; Model II assumed three additive QTLs plus one pair of epistatic QTLs; and Model III assumed two additive QTLs with opposite genetic effects plus two pairs of epistatic QTLs. Recombinant inbred lines (RILs) (50-1500 samples) were simulated according to the Models to study the influence of different sample sizes under different genetic models on QTL mapping accuracy. RILs with 10-100 target chromosome markers were simulated according to Models I and II to evaluate the influence of marker density on QTL mapping accuracy. Different marker densities did not significantly influence accurate estimation of genetic effects with simple additive models, but influenced QTL mapping accuracy in the additive and epistatic models. The optimum marker density was approximately 20 markers when the recombination fraction between two adjacent markers was 0.056 in the additive and epistatic models. A sample size of 150 was sufficient for detecting simple additive QTLs. Thus, a sample size of approximately 450 is needed to detect QTLs with additive and epistatic models. Sample size must be approximately 750 to detect QTLs with additive, epistatic, and combined effects between QTLs. The sample size should be increased to >750 if the genetic models of the data set become more complicated than Model III. Our results provide a theoretical basis for marker-assisted selection breeding and molecular design breeding.


Recoverin: a potent uveitogen for the induction of photoreceptor degeneration in Lewis rats.
Recoverin is a calcium-binding protein identified as an autoantigen in a paraneoplastic degenerative disease of the human retina known as cancer-associated retinopathy (CAR). In this study we investigated whether recoverin could elicit an immune response leading to the degeneration of photoreceptor cells in a rodent retina, and whether an animal model of CAR could be developed. Injection of Lewis rats with recoverin caused degeneration of the photoreceptor cells. Several features of uveoretinitis were observed, including vitreous cells, perivasculitis, retinal lesions and complete loss of the photoreceptor cell layer. The first clinical signs of retinal inflammation were observed 10-14 days after immunization. The earliest histological changes in the retina also were observed 14 days after immunization. Infiltration of the photoreceptor cell layer and inner layers of the retina with lymphocytic and some polymorphonuclear cells was frequently observed. Photoreceptors were damaged and later fully degenerated. This sequence of events was associated with high antibody titers against recoverin in all animals tested. Cellular responses to recoverin assayed between days 7 and 28 after immunization showed strong in vitro proliferative activities to recoverin. In addition, all aspects of the degenerative events could be reproduced in naive animals by the adoptive transfer of stimulated lymphocytes obtained from animals previously immunized with recoverin. This study demonstrates the successful induction of photoreceptor degeneration using recoverin as an immunogen. We demonstrate that recoverin is both a potent antigen and uveitogen. These observations may be relevant to our understanding of CARs in humans.


Kalirin binds the NR2B subunit of the NMDA receptor, altering its synaptic localization and function.
The ability of dendritic spines to change size and shape rapidly is critical in modulating synaptic strength; these morphological changes are dependent upon rearrangements of the actin cytoskeleton. Kalirin-7 (Kal7), a Rho guanine nucleotide exchange factor localized to the postsynaptic density (PSD), modulates dendritic spine morphology in vitro and in vivo. Kal7 activates Rac and interacts with several PSD proteins, including PSD-95, DISC-1, AF-6, and Arf6. Mice genetically lacking Kal7 (Kal7(KO)) exhibit deficient hippocampal long-term potentiation (LTP) as well as behavioral abnormalities in models of addiction and learning. Purified PSDs from Kal7(KO) mice contain diminished levels of NR2B, an NMDA receptor subunit that plays a critical role in LTP induction. Here we demonstrate that Kal7(KO) animals have decreased levels of NR2B-dependent NMDA receptor currents in cortical pyramidal neurons as well as a specific deficit in cell surface expression of NR2B. Additionally, we demonstrate that the genotypic differences in conditioned place preference and passive avoidance learning seen in Kal7(KO) mice are abrogated when animals are treated with an NR2B-specific antagonist during conditioning. Finally, we identify a stable interaction between the pleckstrin homology domain of Kal7 and the juxtamembrane region of NR2B preceding its cytosolic C-terminal domain. Binding of NR2B to a protein that modulates the actin cytoskeleton is important, as NMDA receptors require actin integrity for synaptic localization and function. These studies demonstrate a novel and functionally important interaction between the NR2B subunit of the NMDA receptor and Kalirin, proteins known to be essential for normal synaptic plasticity.


The impact of family transitions on child fostering in rural Malawi.
Despite the frequency of divorce and remarriage across much of sub-Saharan Africa, little is known about what these events mean for the living arrangements of children. We use longitudinal data from rural Malawi to examine the effects of family transitions on the prevalence and incidence of child fostering, or children residing apart from their living parents. We find that between 7 % and 15 % of children aged 3-14 are out-fostered over the two-year intersurvey period. Although divorce appears to be a significant driver of child fostering in the cross-sectional analysis, it is not significantly associated with the incidence of out-fostering. In contrast, maternal remarriage has both a lagged and an immediate effect on the incidence of out-fostering. Furthermore, the likelihood of out-fostering is even higher among children whose mother remarried and had a new child during the intersurvey period. Using longitudinal data collected from living mothers rather than from children's current foster homes offers new insights into the reasons children are sent to live with others besides their parents.


Children's Oxygen Administration Strategies Trial (COAST): A randomised controlled trial of high flow versus oxygen versus control in African children with severe pneumonia.
Background: In Africa, the clinical syndrome of pneumonia remains the leading cause of morbidity and mortality in children in the post-neonatal period. This represents a significant burden on in-patient services. The targeted use of oxygen and simple, non-invasive methods of respiratory support may be a highly cost-effective means of improving outcome, but the optimal oxygen saturation threshold that results in benefit and the best strategy for delivery are yet to be tested in adequately powered randomised controlled trials. There is, however, an accumulating literature about the harms of oxygen therapy across a range of acute and emergency situations that have stimulated a number of trials investigating permissive hypoxia. Methods: In 4200 African children, aged 2 months to 12 years, presenting to 5 hospitals in East Africa with respiratory distress and hypoxia (oxygen saturation < 92%), the COAST trial will simultaneously evaluate two related interventions (targeted use of oxygen with respect to the optimal oxygen saturation threshold for treatment and mode of delivery) to reduce shorter-term mortality at 48-hours (primary endpoint), and longer-term morbidity and mortality to 28 days in a fractional factorial design, that compares: Liberal oxygenation (recommended care) compared with a strategy that permits hypoxia to SpO 2 > or = 80% (permissive hypoxia); andHigh flow using AIrVO 2TM compared with low flow delivery (routine care). Discussion: The overarching objective is to address the key research gaps in the therapeutic use of oxygen in resource-limited setting in order to provide a better evidence base for future management guidelines. The trial has been designed to address the poor outcomes of children in sub-Saharan Africa, which are associated with high rates of in-hospital mortality, 9-10% (for those with oxygen saturations of 80-92%) and 26-30% case fatality for those with oxygen saturations <80%. Clinical trial registration: ISRCTN15622505 Trial status: Recruiting.


Caries prevalence and distribution in 3-20-year-olds in Jönköping, Sweden, in 1973, 1978, 1983, and 1993.
Four cross-sectional studies were carried out in 1973, 1978, 1983, and 1993 to collect clinical and radiographic epidemiological data on the dental health status of the inhabitants of Jönköping, Sweden. The aim of the present paper was to use these data to analyze trends in the development of caries among children and adolescents between 1973 and 1993. Approximately 500 randomly selected individuals evenly distributed among the age groups 3, 5, 10, 15, and 20 years participated in each study. The main results show that the numbers of caries-free individuals increased in all age groups. In 1993, the mean number of decayed and filled tooth surfaces in the primary (dfs) and the permanent (DFS) dentition in all age groups was less than half of that found in 1973. Most of this decrease took place during the first 5 years, i.e., between 1973 and 1978. Between 1978 and 1983, only minor changes were observed. There was a further reduction of approximately 30%-50% in dfs/DFS between 1983 and 1993 in 3-, 5-, 10-, and 20-year-olds. The frequency distributions of dfs/DFS for 5- and 15-year-olds revealed an increasing skewness over time: in 1993, a large majority of the children and adolescents had a low or moderate caries severity while only a small group had high scores of dfs/DFS.


Emerging understanding of dosimetric factors impacting on dysphagia and nutrition following radiotherapy for oropharyngeal cancer.
Research has reported relationships between 3-dimensional (3D) radiation dose to head and neck structures and consequential swallowing/nutritional outcomes. However, this evidence is preliminary. The current study aimed to identify which reported dose constraints identified functional impairment at 6 months posttreatment. Dose constraints with reported relationships to swallowing and nutrition were identified through a systematic literature review. Dose-volume histograms for 12 patients with T1-T3 oropharyngeal cancer treated with 3D conformal radiotherapy determined dosages delivered to specific structures. Doses were examined in relation to published dose constraints and the swallowing and nutritional outcomes at 6 months posttreatment. In all, 66% of the reported mean, maximum, and partial doses to 8 structures correctly identified swallowing and nutrition outcomes at 6 months. The relationships observed between known dosimetric constraints and functional outcomes highlight the potential for dosimetric data to assist in prognosis and treatment. Systematic research is required to refine dosimetric parameters and the impact on functional outcomes.


Anomalous diffusion and dielectric relaxation in an N-fold cosine potential.
The fractional Klein-Kramers (Fokker-Planck) equation describing the fractal time dynamics of an assembly of fixed axis dipoles rotating in an N-fold cosine potential representing the internal field due to neighboring molecules is solved using matrix continued fractions. The result can be considered as a generalization of the solution for the normal Brownian motion in a cosine periodic potential to fractional dynamics (giving rise to anomalous diffusion) and also represents a generalization of Fröhlich's model of relaxation over a potential barrier. The solution includes both inertial and strong internal field effects, which in combination produce a strong resonance peak (Poley absorption) at high frequencies due to librations of the dipoles in the potential, an anomalous relaxation band at low frequencies mainly arising from overbarrier relaxation, and a weaker relaxation band at midfrequencies due to the fast intrawell modes. The high-frequency behavior is controlled by the inertia of the dipole, so that the Gordon sum rule for dipolar absorption is satisfied, ensuring a return to optical transparency at very high frequencies. Application of the model to the broadband (0-THz) dielectric loss spectrum of a dilute solution of the probe dipolar molecule CH2Cl2 in glassy decalin is demonstrated.


The nuts and bolts of low-level laser (light) therapy.
Soon after the discovery of lasers in the 1960s it was realized that laser therapy had the potential to improve wound healing and reduce pain, inflammation and swelling. In recent years the field sometimes known as photobiomodulation has broadened to include light-emitting diodes and other light sources, and the range of wavelengths used now includes many in the red and near infrared. The term "low level laser therapy" or LLLT has become widely recognized and implies the existence of the biphasic dose response or the Arndt-Schulz curve. This review will cover the mechanisms of action of LLLT at a cellular and at a tissular level and will summarize the various light sources and principles of dosimetry that are employed in clinical practice. The range of diseases, injuries, and conditions that can be benefited by LLLT will be summarized with an emphasis on those that have reported randomized controlled clinical trials. Serious life-threatening diseases such as stroke, heart attack, spinal cord injury, and traumatic brain injury may soon be amenable to LLLT therapy.


Tobacco control and household tobacco consumption: A tale of two educational groups.
Since the ratification of the World Health Organization Framework Convention on Tobacco Control in 2004, Pakistan has made modest but continued progress in implementing various tobacco control measures. By 2014, substantial progress was achieved in areas of monitoring, mass media antitobacco campaigns, and advertising bans. However, the findings from the 2014 Global Adult Tobacco Survey of Pakistan show significant differences in antitobacco campaign exposure among individuals of different educational attainment. Given this large variation in noticing antitobacco information, this paper analyzes how heterogeneity in treatment exposure may differentially impact tobacco-use prevalence across household groups. Household-level tobacco-use prevalence in 2014 was, respectively, 56% and 48% for the low- and high-education households. The gap in tobacco-use prevalence between the two educational groups further widens post 2014. We find that, on average, individuals with higher than primary education are 14 percentage points and 6 percentage points more likely to notice anticigarette and antismokeless tobacco information in 2014, respectively. Subsequently, in 2016, high-education households experienced a 3.6 percentage point higher reduction in tobacco-use prevalence compared to the low-education households. These findings motivate policies to enhance the outreach of tobacco control measures across different educational groups.


Long-term effects of intermittent androgen suppression on testosterone recovery and bone mineral density: results of a 33-month observational study.
To investigate changes in bone mineral density (BMD) and osteoporosis, over 3 years of intermittent androgen-suppression therapy (IAST). This was a Phase II individual cohort study of 72 patients with prostate cancer without metastatic bone disease, enrolled between 1999 and 2002. Patients had 9 months flutamide (250 mg, three times daily) and leuprolide (22.5 mg, 3-monthly depot) after which, patients ceased therapy providing that their PSA levels were <4 ng/mL. AST re-commenced when the PSA level exceeded the pretreatment level or was >20 ng/mL. BMD for hip and spine was the primary endpoint; assessed at baseline; completion of initial treatment period; and at 1 and 2 years after initial treatment (POST period). Osteoporosis increased from 7% at baseline to 10% at 3 years. The BMD declined after 9 months treatment, at -1.9% and -3.3% at hip and spine, respectively (P < 0.001). Subsequent BMD decline in the POST period was attenuated; at 1 years and 2 years later, hip -0.6% (not significant), and -0.8% (P < 0.014), and spine +1.0% and +0.2% (not significant). The BMD change in those remaining 'off' therapy for 2 years (n = 20) was strongly associated with the level of testosterone recovery; a peak testosterone level of <5 nmol/L associated with a greater then normal physiological loss. Testosterone recovery was less likely in older men. The attenuation of spine and hip BMD decline after 3-year IAST compared with those reported for continuous AST appears to be due to testosterone driven BMD recovery in the POST period. Failure of testosterone recovery was associated with worse final BMD. By reducing the potential risk for adverse bone complications, intermittent therapy may become an important consideration when the therapeutic ratio is narrow.


HLA-DPB1*04:01 Protects Genetically Susceptible Children from Celiac Disease Autoimmunity in the TEDDY Study.
Tissue transglutaminase autoantibodies (tTGAs) represent the first evidence of celiac disease (CD) development. Associations of HLA-DR3-DQA1*05:01-DQB1*02:01 (i.e., DR3-DQ2) and, to a lesser extent, DR4-DQA1*03:01-DQB1*03:02 (i.e., DR4-DQ8) with the risk of CD differ by country, consistent with additional genetic heterogeneity that further refines risk. Therefore, we examined human leukocyte antigen (HLA) factors other than DR3-DQ2 for their contribution to developing tTGAs. The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8,676 infants at an increased HLA-DR-DQ risk for type 1 diabetes and CD into a 15-year prospective surveillance follow-up. Of those followed up, 21% (n=1,813) carried DR3-DQ2/DR3-DQ2, 39% (n=3,359) carried DR3-DQ2/DR4-DQ8, 20% (n=1701) carried DR4-DQ8/DR4-DQ8, and 17% (n=1,493) carried DR4-DQ8/DQ4. Within TEDDY, a nested case-control design of 248 children with CD autoimmunity (CDA) and 248 matched control children were genotyped for HLA-B, -DRB3, -DRB4, -DPA1, and -DPB1 genes, and the entire cohort was genotyped for single-nucleotide polymorphisms (SNPs) using the Illumina ImmunoChip. CDA was defined as a positive tTGA test at two consecutive clinic visits, whereas matching in those with no evidence of tTGAs was based on the presence of HLA-DQ2, country, and sex. After adjustment for DR3-DQ2 and restriction to allele frequency (AF) ≥5%, HLA-DPB1*04:01 was inversely associated with CDA by conditional logistic regression (AF=44%, odds ratio=0.71, 95% confidence interval (CI)=0.53-0.96, P=0.025). This association of time to CDA and HLA-DPB1*04:01 was replicated with statistical significance in the remainder of the cohort using imputation for specific HLA alleles based on SNP genotyping (hazard ratio=0.84, 95% CI=0.73-0.96, P=0.013). HLA-DPB1*04:01 may reduce the risk of tTGAs, an early marker of CD, among DR3-DQ2 children, confirming that additional variants in the HLA region influence the risk for CDA.


Nongrowing season methane emissions-a significant component of annual emissions across northern ecosystems.
Wetlands are the single largest natural source of atmospheric methane (CH4 ), a greenhouse gas, and occur extensively in the northern hemisphere. Large discrepancies remain between "bottom-up" and "top-down" estimates of northern CH4 emissions. To explore whether these discrepancies are due to poor representation of nongrowing season CH4 emissions, we synthesized nongrowing season and annual CH4 flux measurements from temperate, boreal, and tundra wetlands and uplands. Median nongrowing season wetland emissions ranged from 0.9 g/m2 in bogs to 5.2 g/m2 in marshes and were dependent on moisture, vegetation, and permafrost. Annual wetland emissions ranged from 0.9 g m-2 year-1 in tundra bogs to 78 g m-2 year-1 in temperate marshes. Uplands varied from CH4 sinks to CH4 sources with a median annual flux of 0.0 ± 0.2 g m-2 year-1 . The measured fraction of annual CH4 emissions during the nongrowing season (observed: 13% to 47%) was significantly larger than that was predicted by two process-based model ensembles, especially between 40° and 60°N (modeled: 4% to 17%). Constraining the model ensembles with the measured nongrowing fraction increased total nongrowing season and annual CH4 emissions. Using this constraint, the modeled nongrowing season wetland CH4 flux from >40° north was 6.1 ± 1.5 Tg/year, three times greater than the nongrowing season emissions of the unconstrained model ensemble. The annual wetland CH4 flux was 37 ± 7 Tg/year from the data-constrained model ensemble, 25% larger than the unconstrained ensemble. Considering nongrowing season processes is critical for accurately estimating CH4 emissions from high-latitude ecosystems, and necessary for constraining the role of wetland emissions in a warming climate.


A Herpes Zoster Outbreak on the Sinai Peninsula.
Infection with the varicella zoster virus, a type of herpesvirus, causes chickenpox in children and herpes zoster (commonly known as shingles) in adults. Two 20-year-old male Soldiers returned from an outpost with a rash consistent with herpes zoster. Two other Soldiers with whom they were in close had had a similar rash 2 weeks earlier, which had since resolved at the time of initial presentation. Management and Outcome: Both Soldiers were started on an antiviral regimen and released to duty. They reported progressive relief, but both Soldiers redeployed to the United States before complete resolution. Herpes zoster cannot be transmitted from person to person. It is rare for young healthy people to become afflicted with it, let alone for two people to get it at the same time, which initially raised concern for infections mimicking herpes zoster. However, herpes zoster may be triggered by acute stress. Providers in deployed areas should consider the diagnosis in personnel who have had childhood varicella zoster infection (chickenpox).


Can succinylcholine be used safely in hyperkalemic patients?
The use of succinylcholine in hyperkalemic patients (serum potassium >5.5 mEq/L) is often viewed as relatively contraindicated, although there are no systematic data to define what preoperative potassium level is safe. We retrospectively reviewed more than 40,000 general anesthetics administered over 70 mo in which succinylcholine was given at the induction. This search yielded 38 patients with a preoperative potassium of 5.6 mEq/L or greater. Survival of the anesthetic was 100%, and no dysrhythmias or other major morbidity were documented upon manual review of the intraoperative automated record keeper charts or the patient medical records. These data allow a 95% confidence interval assessment of maximal risk for an event of 7.9%, which is not negligible, but which almost certainly grossly overestimates the risk for patients with moderately increased potassium levels. A prospective trial to definitively assess the safety margin for succinylcholine use in hyperkalemic patients would be difficult. Therefore, these data, taken in the context of a compelling case for rapid intubating conditions without long-term paralysis, suggest safety in succinylcholine use in patients with modest hyperkalemia. In a review of more than 40,000 general anesthetics in which succinylcholine was given at induction, 38 patients had a preoperative potassium of 5.6 mEq/L or greater. All patients survived the anesthetic with no dysrhythmias or other major morbidity documented. Succinylcholine may be appropriate and safe for use in certain patients with moderate hyperkalemia.


Depression, suicidality, and alcohol use disorder among people living with HIV/AIDS in Nigeria.
People Living with HIV/AIDS (PLHIV) face various day-to-day and long-term personal, interpersonal, social, physical and psychological challenges as a result of, and in addition to the health conditions they are susceptible to due to their HIV status. There is a dearth of large-scale research to provide robust prevalence estimates of mental health problems among PLHIV, especially in Nigeria. This study aimed to ascertain the prevalence and factors associated with major depressive episodes, suicidality, and alcohol use disorder among people living with HIV/AIDS in Nigeria. A survey of 1187 participants aged 18 years and above was conducted within three HIV treatment centres in Abuja, Nigeria. Depression, suicidality, and alcohol use disorder modules of the WHO World Mental Health Composite International Diagnostic Interview questionnaire were used for this study. A socio-demographic questionnaire was also used to collect other health and demographic data. Descriptive statistics (frequency distribution, percentage, mean, median, mode, and standard deviation) and regression analyses were conducted to explore associations between mental health problems and demographic and other health-related factors. Twelve-month prevalence rates were 28.2% for major depressive episodes, 2.9% for suicidal ideation, 2.3% for suicide attempts, 7.8% for harmful alcohol use, 7.0% for alcohol abuse, and 2.2% for alcohol dependence. Major depressive episodes were significantly associated with having planned suicide and marital status. Suicidal ideation was significantly associated with major depressive episodes, marital status, and religion. Females were less likely to be diagnosed with alcohol disorders. Some people living with HIV/AIDS also tend to suffer from depression, suicidality, and alcohol use disorders. These findings highlight the need for the integration of mental health services into HIV/AIDS care in Nigeria.


Socioeconomic determinants of risk of harmful alcohol drinking among people aged 50 or over in England.
This paper looks into the socioeconomic determinants of risk of harmful alcohol drinking and of the transitions between risk categories over time among the population aged 50 or over in England. Community-dwellers across England. Respondents to the English Longitudinal Survey of Ageing, waves 4 and 5. (Confidence level at 95% or higher, except when stated): ▸ Higher risk drinking falls with age and there is a non-linear association between age and risk for men, peaking in their mid-60s. ▸ Retirement and income are positively associated with a higher risk for women but not for men. ▸ Education and smoking are positively associated for both sexes. ▸ Loneliness and depression are not associated. ▸ Caring responsibilities reduce risk among women. ▸ Single, separated or divorced men show a greater risk of harmful drinking (at 10% confidence level). ▸ For women, being younger and having a higher income at baseline increase the probability of becoming a higher risk alcohol drinker over time. ▸ For men, not eating healthily, being younger and having a higher income increase the probability of becoming a higher risk alcohol drinker. Furthermore, the presence of children living in the household, being lonely, being older and having a lower income are associated with ceasing to be a higher risk alcohol drinker over time. Several socioeconomic factors found to be associated with high-risk alcohol consumption behaviour among older people would align with those promoted by the 'successful ageing' policy framework.


Bioorthogonal Copper Free Click Chemistry for Labeling and Tracking of Chondrocytes In Vivo.
Establishment of an appropriate cell labeling and tracking method is essential for the development of cell-based therapeutic strategies. Here, we are introducing a new method for cell labeling and tracking by combining metabolic gylcoengineering and bioorthogonal copper-free Click chemistry. First, chondrocytes were treated with tetraacetylated N-azidoacetyl-D-mannosamine (Ac4ManNAz) to generate unnatural azide groups (-N3) on the surface of the cells. Subsequently, the unnatural azide groups on the cell surface were specifically conjugated with near-infrared fluorescent (NIRF) dye-tagged dibenzyl cyclooctyne (DBCO-650) through bioorthogonal copper-free Click chemistry. Importantly, DBCO-650-labeled chondrocytes presented strong NIRF signals with relatively low cytotoxicity and the amounts of azide groups and DBCO-650 could be easily controlled by feeding different amounts of Ac4ManNAz and DBCO-650 to the cell culture system. For the in vivo cell tracking, DBCO-650-labeled chondrocytes (1 × 10(6) cells) seeded on the 3D scaffold were subcutaneously implanted into mice and the transplanted DBCO-650-labeled chondrocytes could be effectively tracked in the prolonged time period of 4 weeks using NIRF imaging technology. Furthermore, this new cell labeling and tracking technology had minimal effect on cartilage formation in vivo.


Fluorescent carbon dots with tunable emission by dopamine for sensing of intracellular pH, elementary arithmetic operations and a living cell imaging based INHIBIT logic gate.
Fluorescent carbon dots (C-dots) have drawn great attention in recent years, and many researchers have focused on developing preparation routes and broadening the applications of C-dots. In this work, novel luminescent C-dots with tunable emission were prepared by the pyrolysis of citric acid (CA) and dopamine (DA). By adjusting the molar ratio of CA and DA in the precursor from 2 : 1 to 2 : 3, the maximum fluorescence emission of the obtained C-dots is at 510 nm in acid solution, while it shifts to 450 nm under neutral conditions, and the fluorescence is quenched in a basic solution. By controlling the unique fluorescence emission at different pH values, a three-state switch is achieved. Half-addition and half-subtraction were performed at 525 nm and 450 nm emissions as outputs. And a living cell imaging based INHIBIT logic gate operation was achieved by imaging the channel ratio of the cells.


Identification of the essential protein domains for Mib2 function during the development of the Drosophila larval musculature and adult flight muscles.
The proper differentiation and maintenance of myofibers is fundamental to a functional musculature. Disruption of numerous mostly structural factors leads to perturbations of these processes. Among the limited number of known regulatory factors for these processes is Mind bomb2 (Mib2), a muscle-associated E3 ubiquitin ligase, which was previously established to be required for maintaining the integrity of larval muscles. In this study, we have examined the mechanistic aspects of Mib2 function by performing a detailed functional dissection of the Mib2 protein. We show that the ankyrin repeats, in its entirety, and the hitherto uncharacterized Mib-specific domains (MIB), are important for the major function of Mib2 in skeletal and visceral muscles in the Drosophila embryo. Furthermore, we characterize novel mib2 alleles that have arisen from a forward genetic screen aimed at identifying regulators of myogenesis. Two of these alleles are viable, but flightless hypomorphic mib2 mutants, and harbor missense mutations in the MIB domain and RING finger, respectively. Functional analysis of these new alleles, including in vivo imaging, demonstrates that Mib2 plays an additional important role in the development of adult thorax muscles, particularly in maintaining the larval templates for the dorsal longitudinal indirect flight muscles during metamorphosis.


Protein digestibility-corrected amino acid scores and digestible indispensable amino acid scores differentially describe protein quality in growing male rats.
The FAO has recommended replacing the protein digestibility-corrected amino acid score (PDCAAS) with the digestible indispensable amino acid score (DIAAS). The objective of this study was to compare aspects underlying the calculation of the DIAAS and PDCAAS, including 1) fecal digestibility vs. ileal digestibility, 2) using a single nitrogen digestibility value for all amino acids, and 3) the effect of truncation. Truncated PDCAAS and untruncated DIAAS values calculated as formally defined were also compared and DIAAS data presented for 14 dietary protein sources. Semisynthetic wheat starch-based diets were formulated to contain the test protein (as consumed by humans) source (whey- and soy-protein isolates, milk-, whey-, rice- and pea- protein concentrates, cooked kidney beans, roasted peanuts, cooked peas, corn-based breakfast cereal, cooked rice, cooked rolled oats, and wheat bran) as the sole nitrogen source and with an indigestible marker (titanium dioxide). Growing male rats (∼250 g bodyweight) were given a basal casein-based diet from day 1 to day 7 and then allocated (n = 6) to the test diets for day 8 to day 14 before ileal digesta were collected after the rats were killed. Total feces were collected from day 11 to day 14. True fecal nitrogen digestibility was different (P < 0.05; 10% difference on average) from true ileal nitrogen digestibility for 11 of the 14 protein sources. True ileal nitrogen digestibility was different (P < 0.05) from true ileal amino acid digestibility for almost half of the indispensable and conditionally indispensable amino acids (differences ranged from 0.9% to 400%). DIAAS values ranged from 0.01 for a corn-based cereal to 1.18 for milk protein concentrate. Untruncated PDCAAS values were generally higher than a DIAAS values, especially for the poorer quality proteins; therefore, the reported differences in the scores are of potential practical importance for populations in which dietary protein intake may be marginal.


Operando time-resolved X-ray absorption spectroscopy reveals the chemical nature enabling highly selective CO2 reduction.
Copper electrocatalysts have been shown to selectively reduce carbon dioxide to hydrocarbons. Nevertheless, the absence of a systematic study based on time-resolved spectroscopy renders the functional agent-either metallic or oxidative Copper-for the selectivity still undecidable. Herein, we develop an operando seconds-resolved X-ray absorption spectroscopy to uncover the chemical state evolution of working catalysts. An oxide-derived Copper electrocatalyst is employed as a model catalyst to offer scientific insights into the roles metal states serve in carbon dioxide reduction reaction (CO2RR). Using a potential switching approach, the model catalyst can achieve a steady chemical state of half-Cu(0)-and-half-Cu(I) and selectively produce asymmetric C2 products - C2H5OH. Furthermore, a theoretical analysis reveals that a surface composed of Cu-Cu(I) ensembles can have dual carbon monoxide molecules coupled asymmetrically, which potentially enhances the catalyst's CO2RR product selectivity toward C2 products. Our results offer understandings of the fundamental chemical states and insights to the establishment of selective CO2RR.


GeneSigDB--a curated database of gene expression signatures.
The primary objective of most gene expression studies is the identification of one or more gene signatures; lists of genes whose transcriptional levels are uniquely associated with a specific biological phenotype. Whilst thousands of experimentally derived gene signatures are published, their potential value to the community is limited by their computational inaccessibility. Gene signatures are embedded in published article figures, tables or in supplementary materials, and are frequently presented using non-standard gene or probeset nomenclature. We present GeneSigDB (http://compbio.dfci.harvard.edu/genesigdb) a manually curated database of gene expression signatures. GeneSigDB release 1.0 focuses on cancer and stem cells gene signatures and was constructed from more than 850 publications from which we manually transcribed 575 gene signatures. Most gene signatures (n = 560) were successfully mapped to the genome to extract standardized lists of EnsEMBL gene identifiers. GeneSigDB provides the original gene signature, the standardized gene list and a fully traceable gene mapping history for each gene from the original transcribed data table through to the standardized list of genes. The GeneSigDB web portal is easy to search, allows users to compare their own gene list to those in the database, and download gene signatures in most common gene identifier formats.


Unified analysis of the sensitivities of reflectance and path length to scattering variations in a diffusive medium.
A unified analysis is presented for the sensitivities of reflectance and path length to scattering variations in a diffusive medium, using an improved solution of the steady-state diffusion equation. This approach enables one to (1) explain theoretically two kinds of dependency of near-infrared reflectance on source-detector separations and (2) obtain an analytical expression for optical path lengths. The results shown here are consistent with those of Kumar and Schmitt [Appl. Opt. 36, 2286 (1997)] and Mourant et al. [Appl. Opt. 36, 5655 (1997)]. Also, discussions are given on (1) possible reasons for some inconsistency between the conclusion drawn by Mourant et al. and results given here and (2) the usefulness of making reflectance measurements while minimizing the sensitivity of reflectance and path length to scattering variations.


Impact of distal side water and residue 315 on ligand binding to ferric Mycobacterium tuberculosis catalase-peroxidase (KatG).
The catalase-peroxidase (KatG) of Mycobacterium tuberculosis (Mtb) is important for the virulence of this pathogen and also is responsible for activation of isoniazid (INH), an antibiotic in use for over 50 years in the first line treatment against tuberculosis infection. Overexpressed Mtb KatG contains a heterogeneous population of heme species that present distinct spectroscopic properties and, as described here, functional properties. A six-coordinate (6-c) heme species that accumulates in the resting enzyme after purification is defined as a unique structure containing weakly associated water on the heme distal side. We present the unexpected finding that this form of the enzyme, generally present as a minority species along with five-coordinate (5-c) enzyme, is the favored reactant for ligand binding. The use of resting enzyme samples with different proportional composition of 5-c and 6-c forms, as well as the use of KatG mutants with replacements at residue 315 that have different tendencies to stabilize the 6-c form, allowed demonstration of more rapid cyanide binding and preferred peroxide binding to enzyme containing 6-c heme. Optical-stopped flow and equilibrium titrations of ferric KatG with potassium cyanide reveal complex behavior that depends in part on the amount of 6-c heme in the resting enzymes. Resonance Raman and low-temperature EPR spectroscopy clearly demonstrate favored ligand (cyanide or peroxide) binding to 6-c heme. The 5-c and 6-c enzyme forms are not in equilibrium on the time scale of the experiments. The results provide evidence for the likely participation of specific water molecule(s) in the first phases of the reaction mechanism of catalase-peroxidase enzymes.


Receiving early information and trusting Swedish child health centre nurses increased parents' willingness to vaccinate against rotavirus infections.
Rotavirus vaccines are effective against severe infections, but have a modest impact on mortality in high-income countries. Parental knowledge and attitudes towards vaccines are crucial for high vaccination coverage. This study aimed to identify why parents refused to let their infant have the vaccination or were unsure. This cross-sectional study was based on 1,063 questionnaires completed by the parents of newborn children in 2014. Stepwise logistic regression was used to identify the main predictors. Most (81%) parents intended to vaccinate their child against the rotavirus, while 19% were unwilling or uncertain. Parents with less education and children up to five weeks of age were more likely to be unwilling or uncertain about vaccinating their child. Factors associated with a refusal or uncertainty about vaccinating were not having enough information about the vaccine, no intention of accepting other vaccines, paying little heed to the child health nurses' recommendations, thinking that the rotavirus was not a serious illness and not believing that the vaccine provided protection against serious forms of gastroenteritis. Early information, extra information for parents with less education and close positive relationships between parents and child health nurses were important factors in high rotavirus vaccination rates.


Immunohistochemical demonstration of isozyme- and strain-specific differences in the intralobular localizations and distributions of UDP-glucuronosyltransferases in livers of untreated rats.
Antibodies directed against three isozymes of rat hepatic microsomal UDP-glucuronosyltransferase (EC 184.108.40.206), p-nitrophenol, 3 alpha-hydroxysteroid, and 17 beta-hydroxysteroid UDP-glucuronosyltransferases were used to localize these enzymes at the light microscopic level in livers of untreated Sprague-Dawley and Wistar rats. Avidin-biotin-peroxidase staining revealed the presence of each isozyme within parenchymal cells throughout the liver lobule in rats of both strains. However, although antibodies to the 3 alpha- and 17 beta-hydroxysteroid UDP-glucuronosyltransferases appeared to stain hepatocytes across the liver lobule quite uniformly, centrilobular hepatocytes were stained much more intensely for p-nitrophenol UDP-glucuronosyltransferase than were midzonal and periportal cells. Additionally, appreciable immunohistochemical staining for p-nitrophenol UDP-glucuronosyltransferase, but not for the two hydroxysteroid UDP-glucuronosyltransferases, was detected within the epithelium of the hepatic bile duct and the endothelium of the hepatic artery and portal vein. Another difference was noted in livers of Wistar rats: hepatocytes of rats possessing low 3 alpha-hydroxysteroid (i.e., androsterone) UDP-glucuronosyltransferase activity were stained much less intensely for the 3 alpha-hydroxysteroid UDP-glucuronosyltransferase than were those of rats exhibiting high rates of androsterone glucuronidation, whereas differences in immunoperoxidase staining for p-nitrophenol and 17 beta-hydroxysteroid UDP-glucuronosyltransferases were not apparent between the two subclasses of Wistar rats. These immunohistochemical findings demonstrate that different UDP-glucuronosyltransferase isozymes are distributed across the liver lobule in significantly different manners and, furthermore, suggest that xenobiotics may be glucuronidated within epithelial cells of the hepatic bile duct and endothelial cells of the hepatic artery and portal vein, as well as within hepatocytes. The results of this study also provide evidence that differences in the content of 3 alpha-hydroxysteroid UDP-glucuronosyltransferase within hepatocytes account for genetically determined variations in the rates at which androsterone and certain other xenobiotics are glucuronidated in livers of Wistar rats.


Structural Basis of the Enhanced Pollutant-Degrading Capabilities of an Engineered Biphenyl Dioxygenase.
Biphenyl dioxygenase, the first enzyme of the biphenyl catabolic pathway, is a major determinant of which polychlorinated biphenyl (PCB) congeners are metabolized by a given bacterial strain. Ongoing efforts aim to engineer BphAE, the oxygenase component of the enzyme, to efficiently transform a wider range of congeners. BphAEII9, a variant of BphAELB400 in which a seven-residue segment, (335)TFNNIRI(341), has been replaced by the corresponding segment of BphAEB356, (333)GINTIRT(339), transforms a broader range of PCB congeners than does either BphAELB400 or BphAEB356, including 2,6-dichlorobiphenyl, 3,3'-dichlorobiphenyl, 4,4'-dichlorobiphenyl, and 2,3,4'-trichlorobiphenyl. To understand the structural basis of the enhanced activity of BphAEII9, we have determined the three-dimensional structure of this variant in substrate-free and biphenyl-bound forms. Structural comparison with BphAELB400 reveals a flexible active-site mouth and a relaxed substrate binding pocket in BphAEII9 that allow it to bind different congeners and which could be responsible for the enzyme's altered specificity. Biochemical experiments revealed that BphAEII9 transformed 2,3,4'-trichlorobiphenyl and 2,2',5,5'-tetrachlorobiphenyl more efficiently than did BphAELB400 and BphAEB356 BphAEII9 also transformed the insecticide dichlorodiphenyltrichloroethane (DDT) more efficiently than did either parental enzyme (apparent kcat/Km of 2.2 ± 0.5 mM(-1) s(-1), versus 0.9 ± 0.5 mM(-1) s(-1) for BphAEB356). Studies of docking of the enzymes with these three substrates provide insight into the structural basis of the different substrate selectivities and regiospecificities of the enzymes. Biphenyl dioxygenase is the first enzyme of the biphenyl degradation pathway that is involved in the degradation of polychlorinated biphenyls. Attempts have been made to identify the residues that influence the enzyme activity for the range of substrates among various species. In this study, we have done a structural study of one variant of this enzyme that was produced by family shuffling of genes from two different species. Comparison of the structure of this variant with those of the parent enzymes provided an important insight into the molecular basis for the broader substrate preference of this enzyme. The structural and functional details gained in this study can be utilized to further engineer desired enzymatic activity, producing more potent enzymes.


Modified P elements that mimic the P cytotype in Drosophila melanogaster.
Activity of the P family of transposable elements in Drosophila melanogaster is regulated primarily by a cellular condition known as P cytotype. It has been hypothesized that P cytotype depends on a P element-encoded repressor of transposition and excision. We provide evidence in support of this idea by showing that two modified P elements, each with lesions affecting the fourth transposase exon, mimic most of the P cytotype effects. These elements were identified by means of two sensitive assays capable of detecting repression by a single P element. One assay makes use of cytotype-dependent gene expression of certain P element insertion mutations at the singed bristle locus. The other measures suppression of transposase activity from the unusually stable genomic P element, delta 2-3(99B), that normally produces transposase in both germinal and somatic tissues. The P cytotype-like effects include suppression of snw germline hypermutability, snw somatic mosaicism, pupal lethality, and gonadal dysgenic sterility. Unlike P cytotype, however, there was no reciprocal cross effect in the inheritance of repression.


Contributions of voltage- and Ca2+-activated conductances to GABA-induced depolarization in spider mechanosensory neurons.
Activation of ionotropic gamma-aminobutyric acid type A (GABA(A)) receptors depolarizes neurons that have high intracellular [Cl(-)], causing inhibition or excitation in different cell types. The depolarization often leads to inactivation of voltage-gated Na channels, but additional ionic mechanisms may also be affected. Previously, a simulated model of spider VS-3 mechanosensory neurons suggested that although voltage-activated Na(+) current is partially inactivated during GABA-induced depolarization, a slowly activating and inactivating component remains and may contribute to the depolarization. Here, we confirmed experimentally, by blocking Na channels prior to GABA application, that Na(+) current contributes to GABA-induced depolarization in VS-3 neurons. Ratiometric Ca(2+) imaging experiments combined with intracellular recordings revealed a significant increase in intracellular [Ca(2+)] when GABA(A) receptors were activated, synchronous with the depolarization and probably due to Ca(2+) influx via low-voltage-activated (LVA) Ca channels. In contrast, GABA(B)-receptor activation in these neurons was previously shown to inhibit LVA current. Blockade of voltage-gated K channels delayed membrane repolarization, extending GABA-induced depolarization. However, inhibition of Ca channels significantly increased the amplitude of GABA-induced depolarization, indicating that Ca(2+)-activated K(+) current has an even stronger repolarizing effect. Regulation of intracellular [Ca(2+)] is important for many cellular processes and Ca(2+) control of K(+) currents may be particularly important for some functions of mechanosensory neurons, such as frequency tuning. These data show that GABA(A)-receptor activation participates in this regulation.


Laser-capture microdissection and transcriptional profiling of the dorsomedial nucleus of the hypothalamus.
Identifying neuronal molecular markers with restricted patterns of expression is a crucial step in dissecting the numerous pathways and functions of the brain. While the dorsomedial nucleus of the hypothalamus (DMH) has been implicated in a host of physiological processes, current functional studies have been limited by the lack of molecular markers specific for DMH. Identification of such markers would facilitate the development of mouse models with DMH-specific genetic manipulations. Here we used a combination of laser-capture microdissection (LCM) and gene expression profiling to identify genes that are highly expressed within the DMH relative to adjacent hypothalamic regions. Six of the most highly expressed of these genes, Gpr50, 4930511J11Rik, Pcsk5, Grp, Sulf1, and Rorβ, were further characterized by real-time polymerase chain reaction (PCR) analysis and in situ hybridization histochemistry. The genes identified in this article will provide the basis for future gene-targeted approaches for studying DMH function.


Three-dimensional optoelectronic stacked processor by use of free-space optical interconnection and three-dimensional VLSI chip stacks.
We present a demonstration system under the three-dimensional (3D) optoelectronic stacked processor consortium. The processor combines the advantages of optics in global, high-density, high-speed parallel interconnections with the density and computational power of 3D chip stacks. In particular, a compact and scalable optoelectronic switching system with a high bandwidth is designed. The system consists of three silicon chip stacks, each integrated with a single vertical-cavity-surface-emitting-laser-metal-semiconductor-metal detector array and an optical interconnection module. Any input signal at one end stack can be switched through the central crossbar stack to any output channel on the opposite end stack. The crossbar bandwidth is designed to be 256 Gb/s. For the free-space optical interconnection, a novel folded hybrid micro-macro optical system with a concave reflection mirror has been designed. The optics module can provide a high resolution, a large field of view, a high link efficiency, and low optical cross talk. It is also symmetric and modular. Off-the-shelf macro-optical components are used. The concave reflection mirror can significantly improve the image quality and tolerate a large misalignment of the optical components, and it can also compensate for the lateral shift of the chip stacks. Scaling of the macrolens can be used to adjust the interconnection length between the chip stacks or make the system more compact. The components are easy to align, and only passive alignment is required. Optics and electronics are separated until the final assembly step, and the optomechanic module can be removed and replaced. By use of 3D chip stacks, commercially available optical components, and simple passive packaging techniques, it is possible to achieve a high-performance optoelectronic switching system.


Association between Psychopathological Dimensions and Sexual Functioning/Sexual Arousal in Young Adults.
Psychological-psychiatric factors have a different effect on sexual functioning in men and women. This research aimed to examine the association between psychopathological dimensions and dimensions of sexual functioning in Spanish young adults in two studies. Study 1 examined sexual functioning and psychopathological dimensions in 700 women and 516 men. Study 2 conducted an experimental laboratory task to evaluate subjective sexual arousal and genital sensations when watching visual sexual stimuli in a subsample of participants from Study 1 (143 women and 123 men). As a result, the first study showed that depression and anxiety-related symptoms had a negative effect, both in men and women, and having a partner had a positive influence on the dimensions of sexual functioning. The second study showed that anxiety symptoms were positively associated with subjective sexual arousal in both men and women, and anxiety was associated with the assessment of genital sensations in men. The differences between the results of anxiety may be explained because sexual arousal was evaluated in general terms in Study 1, whereas it was evaluated as a state in Study 2. These findings confirm that the presence of psychopathological symptoms contributes to sexual functioning, as well as the necessity of strengthening mental illness prevention programs that include sexual health components.


Sustainability literacy of older people in retirement villages.
With many developed countries experiencing the aging of the population, older people play a large role in contributing to environmental problems but also to environmental solutions. The purpose of this research is to understand the awareness and behavior of current older people living in retirement villages towards sustainability development. To achieve this, a sustainability literacy survey was conducted with 65 older residents of a private retirement village located 10 Km outside the Brisbane, Australia's central business district (CBD). Most of residents recognized the importance of environment protection and would like to lead a more environmentally friendly lifestyle. In addition, the majority were willing to pay higher prices for a living environment with sustainable features. The importance of positive social communications was emphasized with most residents having established good relationships with others in the village. The findings provide an important insight into consumer perspectives regarding the sustainable features that should and can be incorporated into the village planning and development.


Knowledge gaps and research priorities in the prevention and control of hepatitis E virus infection.
Hepatitis E virus (HEV), family Hepeviridae, is a main cause of epidemic hepatitis in developing countries and sporadic and cluster cases of hepatitis in industrialized countries. There are an increasing number of reported cases in humans especially in industrialized countries, and there is a high potential for transboundary spread of zoonotic genotypes of the virus through the transport of pigs, pig products and by-products. Bloodborne transmission of the virus has been reported with a significant medical concern. To better coordinate HEV research and design better control measures of HEV infections in animals, a group of HEV experts reviewed the current knowledge on the disease and considered the existing disease control tools. It was concluded that there is a lack of in-depth information about the spread of the virus from pigs to humans. The role of animals other than pigs in the zoonotic transmission of the virus to humans and the extent of foodborne transmission are poorly understood. Factors involved in development of clinical disease such as infectious dose, susceptibility and virulence of virus strains need to be studied more extensively. However, such studies are greatly hindered by the absence of a broadly applicable, efficient and sensitive in vitro cell culture system for HEV. Diagnostic tools for HEV are available but need to be further validated, harmonized and standardized. Commercially available HEV vaccines for the control of HEV infection in animal populations are needed as such vaccines can minimize the zoonotic risk for humans. Anti-HEV drugs for treatment of HEV-infected patients need to be studied more extensively. The detailed expert review can be downloaded from the project website at http://www.discontools.eu/.


Relationship between world-ranking and Olympic performance of swimmers.
Coaches believe world-ranking lists are a reliable tool for predicting international swimming performance. To examine the relationship between world-ranking and Olympic performance, we modelled world-ranking time and best time from the 2000 Olympic Games for 407 top-50 world-ranked swimmers. Analysis of log-transformed times yielded within-athlete and between-athlete coefficients of variation (CV) and percent changes in performance from world-rankings to Olympics. Variations and performance progressions were compared across sex, stroke, distance, nation and medal status. The within-athlete coefficient of variation of performance for all swimmers was 0.8% (95% confidence limits: 0.7 to 0.9%). Females were slightly less consistent, although not substantially different to males (ratio of female/male within-athlete CV: 1.1; 95% confidence limits: 1.0 to 1.2) and had a wider range of talent (ratio of female/male between-athlete CV: 1.2; 95% confidence limits: 1.1 to 1.4). Swimmers from Australia (AUS) were more consistent than those from the United States (USA) and other nations (OTHER) (ratio of within-athlete CV, USA/AUS: 1.5; 95% confidence limits: 1.0 to 2.2; OTHER/ AUS: 1.6; 95% confidence limits: 1.2 to 2.1). Most Olympic medallists (87%) had a top-10 world-ranking. Overall performance time at the Olympics was slower than world-ranking time by 0.3% (95% confidence limits: 0.2 to 0.4%), medallists improved by 0.6% (95% confidence limits: 0.4 to 0.9%) and non-medallists swam 0.6% slower (95% confidence limits: 0.5 to 0.7%). We conclude that a top-10 ranked swimmer who can improve performance time by 0.6%, equivalent to 0.13 s in the men's 50-m freestyle, will substantially increase their chance of an Olympic medal (the difference between first and fourth place).


Beta-catenin deficiency causes DiGeorge syndrome-like phenotypes through regulation of Tbx1.
DiGeorge syndrome (DGS) is a common genetic disease characterized by pharyngeal apparatus malformations and defects in cardiovascular, craniofacial and glandular development. TBX1 is the most likely candidate disease-causing gene and is located within a 22q11.2 chromosomal deletion that is associated with most cases of DGS. Here, we show that canonical Wnt-beta-catenin signaling negatively regulates Tbx1 expression and that mesenchymal inactivation of beta-catenin (Ctnnb1) in mice caused abnormalities within the DGS phenotypic spectrum, including great vessel malformations, hypoplastic pulmonary and aortic arch arteries, cardiac malformations, micrognathia, thymus hypoplasia and mislocalization of the parathyroid gland. In a heterozygous Fgf8 or Tbx1 genetic background, ectopic activation of Wnt-beta-catenin signaling caused an increased incidence and severity of DGS-like phenotypes. Additionally, reducing the gene dosage of Fgf8 rescued pharyngeal arch artery defects caused by loss of Ctnnb1. These findings identify Wnt-beta-catenin signaling as a crucial upstream regulator of a Tbx1-Fgf8 signaling pathway and suggest that factors that affect Wnt-beta-catenin signaling could modify the incidence and severity of DGS.


Urinary Biomarkers of Tubular Damage Are Associated with Mortality but Not Cardiovascular Risk among Systolic Blood Pressure Intervention Trial Participants with Chronic Kidney Disease.
Kidney tubulointerstitial fibrosis on biopsy is a strong predictor of chronic kidney disease (CKD) progression, and CKD is associated with elevated risk of cardiovascular disease (CVD). Tubular health is poorly quantified by traditional kidney function measures, including estimated glomerular filtration rate (eGFR) and albuminuria. We hypothesized that urinary biomarkers of tubular injury, inflammation, and repair would be associated with higher risk of CVD and mortality in persons with CKD. We measured urinary concentrations of interleukin-18 (IL-18), kidney injury molecule-1, neutrophil gelatinase-associated lipocalin, monocyte chemoattractant protein-1, and chitinase-3-like protein-1 (YKL-40) at baseline among 2,377 participants of the Systolic Blood Pressure Intervention Trial who had an eGFR < 60 mL/min/1.73 m2. We used Cox proportional hazards models to evaluate biomarker associations with CVD events and all-cause mortality. At baseline, the mean age of participants was 72 ± 9 years, and eGFR was 48 ± 11 mL/min/1.73 m2. Over a median follow-up of 3.8 years, 305 CVD events (3.6% per year) and 233 all-cause deaths (2.6% per year) occurred. After multivariable adjustment including eGFR, albuminuria, and urinary creatinine, none of the biomarkers showed statistically significant associations with CVD risk. Urinary IL-18 (hazard ratio [HR] per 2-fold higher value, 1.14; 95% CI 1.01-1.29) and YKL-40 (HR per 2-fold higher value, 1.08; 95% CI 1.02-1.14) concentrations were each incrementally associated with higher mortality risk. Associations were similar when stratified by randomized blood pressure arm. Among hypertensive trial participants with CKD, higher urinary IL-18 and YKL-40 were associated with higher risk of mortality, but not CVD.


3,4-Methylenedioxymethamphetamine ("ecstasy") selectively destroys brain serotonin terminals in rhesus monkeys.
3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"), an amphetamine analog, is a "designer drug" which is being increasingly abused. The potential neurotoxic hazard of MDMA in humans was assessed by examining the effects of repeated systemic administration of MDMA on selected neurochemical and behavioral measures in rhesus monkeys. In the first study, MDMA (2.5 or 10 mg/kg twice daily for 4 days) produced selective and significant neurochemical decreases in cerebrospinal fluid (CSF) concentrations of 5-hydroxyindoleacetic acid (5-HIAA) and brain concentrations of serotonin and 5-HIAA. At the high dose of MDMA, a selective decrease in serotonin uptake sites (reflecting destruction of brain serotonin terminals) was observed. To determine if these changes after high dose MDMA were pharmacologic or truly neurotoxic, in a subsequent study monkeys were treated with MDMA (10 mg/kg twice daily for 4 days) and then monitored for 14 weeks. Throughout this period, CSF 5-HIAA was decreased in MDMA-treated animals but not in saline-injected controls. At the end of this period, significant decreases in the concentration of serotonin, 5-HIAA and serotonin uptake sites were observed in cerebral cortex and striatum but not in hypothalamus or spinal cord. In contrast to these widespread alterations in serotonin markers, comparable noradrenergic and dopaminergic measures in CSF and brain appeared generally unaffected. These data demonstrating potent and selective effects of MDMA on various brain serotonin parameters in rhesus monkeys suggest that the drug may produce similar effects in humans.


A comprehensive analysis of genes encoding small secreted proteins identifies candidate effectors in Melampsora larici-populina (poplar leaf rust).
The obligate biotrophic rust fungus Melampsora larici-populina is the most devastating and widespread pathogen of poplars. Studies over recent years have identified various small secreted proteins (SSP) from plant biotrophic filamentous pathogens and have highlighted their role as effectors in host-pathogen interactions. The recent analysis of the M. larici-populina genome sequence has revealed the presence of 1,184 SSP-encoding genes in this rust fungus. In the present study, the expression and evolutionary dynamics of these SSP were investigated to pinpoint the arsenal of putative effectors that could be involved in the interaction between the rust fungus and poplar. Similarity with effectors previously described in Melampsora spp., richness in cysteines, and organization in large families were extensively detailed and discussed. Positive selection analyses conducted over clusters of paralogous genes revealed fast-evolving candidate effectors. Transcript profiling of selected M. laricipopulina SSP showed a timely coordinated expression during leaf infection, and the accumulation of four candidate effectors in distinct rust infection structures was demonstrated by immunolocalization. This integrated and multifaceted approach helps to prioritize candidate effector genes for functional studies.


Flow-regulated endothelial S1P receptor-1 signaling sustains vascular development.
During angiogenesis, nascent vascular sprouts fuse to form vascular networks, enabling efficient circulation. Mechanisms that stabilize the vascular plexus are not well understood. Sphingosine 1-phosphate (S1P) is a blood-borne lipid mediator implicated in the regulation of vascular and immune systems. Here we describe a mechanism by which the G protein-coupled S1P receptor-1 (S1P1) stabilizes the primary vascular network. A gradient of S1P1 expression from the mature regions of the vascular network to the growing vascular front was observed. In the absence of endothelial S1P1, adherens junctions are destabilized, barrier function is breached, and flow is perturbed, resulting in abnormal vascular hypersprouting. Interestingly, S1P1 responds to S1P as well as laminar shear stress to transduce flow-mediated signaling in endothelial cells both in vitro and in vivo. These data demonstrate that blood flow and circulating S1P activate endothelial S1P1 to stabilize blood vessels in development and homeostasis.


Development of a criteria set and a structured interview for disorders of extreme stress (SIDES).
Data regarding the development of a structured interview measuring alterations that may accompany extreme stress are presented. A list of 27 criteria often seen in response to extreme trauma and not addressed by DSM-IV criteria for posttraumatic stress disorder (PTSD) were generated based on a systematic review of the literature and a survey of 50 experts. A structured interview for disorders of extreme stress (SIDES) measuring the presence of these criteria was administered to 520 subjects as part of the DSM-IV PTSD field trials. Inter-rater reliability as measured by Kappa coefficients for lifetime Disorders of Extreme Stress was .81. Internal consistency using coefficient alpha ranged from .53 to .96. Results indicate that the SIDES is a useful tool for investigation of response to extremes stress.


Relevance of different prior knowledge sources for inferring gene interaction networks.
When inferring networks from high-throughput genomic data, one of the main challenges is the subsequent validation of these networks. In the best case scenario, the true network is partially known from previous research results published in structured databases or research articles. Traditionally, inferred networks are validated against these known interactions. Whenever the recovery rate is gauged to be high enough, subsequent high scoring but unknown inferred interactions are deemed good candidates for further experimental validation. Therefore such validation framework strongly depends on the quantity and quality of published interactions and presents serious pitfalls: (1) availability of these known interactions for the studied problem might be sparse; (2) quantitatively comparing different inference algorithms is not trivial; and (3) the use of these known interactions for validation prevents their integration in the inference procedure. The latter is particularly relevant as it has recently been showed that integration of priors during network inference significantly improves the quality of inferred networks. To overcome these problems when validating inferred networks, we recently proposed a data-driven validation framework based on single gene knock-down experiments. Using this framework, we were able to demonstrate the benefits of integrating prior knowledge and expression data. In this paper we used this framework to assess the quality of different sources of prior knowledge on their own and in combination with different genomic data sets in colorectal cancer. We observed that most prior sources lead to significant F-scores. Furthermore, their integration with genomic data leads to a significant increase in F-scores, especially for priors extracted from full text PubMed articles, known co-expression modules and genetic interactions. Lastly, we observed that the results are consistent for three different data sets: experimental knock-down data and two human tumor data sets.


Control of polyaniline deposition on microporous cellulose ester membranes by in situ chemical polymerization.
Polyaniline (PANI) can be deposited either on the surface or in the bulk of a microporous membrane by various chemical oxidative polymerization techniques. Each technique has distinctive effects on the PANI site and extent of deposition on the base membrane. In the present study, mixed cellulose ester (ME) membranes with tortuous pore morphology were used as base membranes. The chemical oxidative polymerization techniques employed, included polymerization using an in-house-built two-compartment permeation cell. The resultant composite membranes have been characterized by scanning electron microscopy (SEM), Fourier-transform infrared spectroscopy (FTIR-ATR), and electrical conductivity measurements. The results showed that PANI was layered on the pore walls of the membrane using two-compartment permeation cell. Vapor-phase polymerization yielded a surface layer of PANI with little deposition in the bulk. A distorted PANI surface layer was achieved by solution-phase (dip) polymerization. Moreover, asymmetric PANI deposition within the membrane bulk was evidenced using two-compartment permeation cell. Composite membranes synthesized using two-compartment cell showed highest levels of conductivity (approximately 10(-2) S/cm) as compared to the membranes modified by single-step solution-phase polymerization. FTIR-ATR results indicated the extent of PANI coating and its oxidation state which was identified as doped emeraldine PANI, from all the employed techniques. Asymmetric deposition and extent have been explained in terms of the physical and chemical reaction steps involved in the heterogeneous aniline polymerization reactions in the two-compartment cell technique.


New forms of citizenship and socio-political inclusion: accessing antiretroviral therapy in a Rio de Janeiro favela.
Brazil has received praise internationally for its national health policy against HIV. Whilst the ethical stance of the Brazilian programme has been widely applauded, there is a lack of empirical data on how the commitment to equitable and universal HIV prevention and treatment works in practice among the poorest population groups. The aim of this paper is to explore the broad ethics of the Brazilian AIDS programme by investigating how universal access to HIV treatment is being implemented within a favela (shanty town). Data collected through anthropological research show that in settings such as the favelas, the universal character of this public health programme is challenged by a number of issues such as local definitions of illness, problems related to the understanding of and adherence to treatment, structural violence, political alienation, and lack of perspectives about the future. It is also argued that such health intervention has contributed to the promotion of novel attitudes towards individual notions of socio-political participation. These are explored with reference to the notion of therapeutic citizenship, which in the context of a favela neighbourhood translates into a new set of concerns around free access to and availability of treatment, the right to health care and the sustainability of public health policies.


Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients.
The prevention of relapse is the major therapeutic challenge in older patients with acute myeloid leukemia (AML) who have obtained a complete remission (CR) on intensive chemotherapy. In this randomized phase 3 study (HOVON97) in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess of blasts, in CR/CR with incomplete hematologic recovery (CRi) after at least 2 cycles of intensive chemotherapy, we assessed the value of azacitidine as postremission therapy with respect to disease-free survival (DFS; primary end point) and overall survival (OS; secondary end point). In total, 116 eligible patients were randomly (1:1) assigned to either observation (N = 60) or azacitidine maintenance (N = 56; 50 mg/m2, subcutaneously, days 1-5, every 4 weeks) until relapse, for a maximum of 12 cycles. Fifty-five patients received at least 1 cycle of azacitidine, 46 at least 4 cycles, and 35 at least 12 cycles. The maintenance treatment with azacitidine was feasible. DFS was significantly better for the azacitidine treatment group (logrank; P = .04), as well as after adjustment for poor-risk cytogenetic abnormalities at diagnosis and platelet count at randomization (as surrogate for CR vs CRi; Cox regression; hazard ratio, 0.62; 95% confidence interval, 0.41-0.95; P = .026). The 12-month DFS was estimated at 64% for the azacitidine group and 42% for the control group. OS did not differ between treatment groups, with and without censoring for allogeneic hematopoietic cell transplantation. Rescue treatment was used more often in the observation group (n = 32) than in the azacitidine maintenance group (n = 9). We conclude that azacitidine maintenance after CR/CRi after intensive chemotherapy is feasible and significantly improves DFS. The study is registered with The Netherlands Trial Registry (NTR1810) and EudraCT (2008-001290-15).


Association between GWAS-identified lung adenocarcinoma susceptibility loci and EGFR mutations in never-smoking Asian women, and comparison with findings from Western populations.
To evaluate associations by EGFR mutation status for lung adenocarcinoma risk among never-smoking Asian women, we conducted a meta-analysis of 11 loci previously identified in genome-wide association studies (GWAS). Genotyping in an additional 10,780 never-smoking cases and 10,938 never-smoking controls from Asia confirmed associations with eight known single nucleotide polymorphisms (SNPs). Two new signals were observed at genome-wide significance (P < 5 × 10-8), namely, rs7216064 (17q24.3, BPTF), for overall lung adenocarcinoma risk, and rs3817963 (6p21.3, BTNL2) which is specific to cases with EGFR mutations. In further sub-analyses by EGFR status, rs9387478 (ROS1/DCBLD1) and rs2179920 (HLA-DPB1) showed stronger estimated associations in EGFR-positive compared to EGFR-negative cases. Comparison of the overall associations with published results in Western populations revealed that the majority of these findings were distinct, underscoring the importance of distinct contributing factors for smoking and non-smoking lung cancer. Our results extend the catalogue of regions associated with lung adenocarcinoma in non-smoking Asian women and highlight the importance of how the germline could inform risk for specific tumour mutation patterns, which could have important translational implications.


[Patterns of use, cannabis beliefs and dependence: study of 159 adolescent users].
To evaluate the connections between the frequency and patterns of cannabis use and dependence, and the beliefs linked to cannabis use in a sample of adolescents. In 2001, 285 high school students (163 boys, 122 girls; mean age = 17.5 +/- 1.1 years) completed questionnaires assessing the patterns of cannabis use, and the symptoms of dependence and abuse, using a questionnaire derived from the Mini International Neuropsychiatric Interview. Cannabis-related beliefs were assessed using the Beliefs Questionnaire for Drug Addiction. Frequency of subjects who reported having used cannabis during the last year was 65.4% of boys and 42.6% of girls. Among users, 53.6% of boys and 39.3% of girls were regular users, 10.6% of boys and 7.8% of girls being daily users. Almost half of the users reported other means of consumption than "joints", in particular water-pipes or "bongs" (34.5% of boys, 26.4% of girls). Among users, near of 33% of boys and girls met the criteria for cannabis dependence. Dependence was more frequent in users practicing other means of consumption than "joints", increasing to 51% for "bong" users. Expectancies of pleasure or relief, and permissive beliefs reflecting the perception of cannabis use as risk free were higher in users and, particularly, in subjects with cannabis dependence. Regression analysis showed that these beliefs were the strongest predictors of cannabis use and dependence. Predictors of use in the total sample were expectancies of pleasure and permissive beliefs, being a male and the age of the subject. Predictors of dependence among users were expectancies of relief, frequency of use, and use of other means of consumption than "joints". Cannabis use in adolescents appeared to be characterized by the frequency of use, consumption by means other than "joints" and by the frequency of dependence. Cannabis use and dependence are linked to expectancies and permissive beliefs that could be targeted for prevention and treatment.


The cellular landscape of mid-size noncoding RNA.
Noncoding RNA plays an important role in all aspects of the cellular life cycle, from the very basic process of protein synthesis to specialized roles in cell development and differentiation. However, many noncoding RNAs remain uncharacterized and the function of most of them remains unknown. Mid-size noncoding RNAs (mncRNAs), which range in length from 50 to 400 nucleotides, have diverse regulatory functions but share many fundamental characteristics. Most mncRNAs are produced from independent promoters although others are produced from the introns of other genes. Many are found in multiple copies in genomes. mncRNAs are highly structured and carry many posttranscriptional modifications. Both of these facets dictate their RNA-binding protein partners and ultimately their function. mncRNAs have already been implicated in translation, catalysis, as guides for RNA modification, as spliceosome components and regulatory RNA. However, recent studies are adding new mncRNA functions including regulation of gene expression and alternative splicing. In this review, we describe the different classes, characteristics and emerging functions of mncRNAs and their relative expression patterns. Finally, we provide a portrait of the challenges facing their detection and annotation in databases. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry RNA Structure and Dynamics > Influence of RNA Structure in Biological Systems RNA Evolution and Genomics > RNA and Ribonucleoprotein Evolution.


Focusing of electromagnetic radiation by hyperboloidal and ellipsoidal lenses.
A solution to the problem of plane electromagnetic waves focused by an ellipsoidal or a hyperboloidal lens is derived from the Stratton-Chu integral by solving a boundary-value problem. The current method is more rigorous than those hitherto published in the literature. Results show that for linearly polarized incident illumination and in the vicinity of the focus, the distribution of the time-averaged electric energy density is almost fully transverse electric.


Working with the "problem" resident: guidelines for definition and intervention.
Clinical teachers often work with residents whom they view as "difficult." For some, it is a knowledge deficit that first alerts them to a problem; for others, it is an attitudinal problem or distressing behavior. The goal of this article is to describe a framework for identifying residents' problems and to outline strategies for intervention. When teachers first suspect a problem, they should try to define the resident's troubling behavior, assess other contributing factors, and evaluate the potential impact of the problem. Following this initial process, teachers should try to confirm their suspicions by determining the resident's perception of the problem, relevant life history, and perceived strengths and weaknesses. They should also examine their own strengths and weaknesses and obtain other teachers' views of the perceived difficulty. In designing an intervention, teachers should carefully define the goal and time frame of the intervention, determine how the problem will be addressed, and decide how the intervention will be documented and evaluated. Although residents' difficulties are often seen as residing within the resident alone, teacher and systems factors must be considered, and the resident should be involved in every step of the process.


The Influence of Training Load on Hematological Athlete Biological Passport Variables in Elite Cyclists.
The hematological module of the Athlete Biological Passport (ABP) is used in elite sport for antidoping purposes. Its aim is to better target athletes for testing and to indirectly detect blood doping. The ABP allows to monitor hematological variations in athletes using selected primary blood biomarkers [hemoglobin concentration (Hb) and reticulocyte percentage (Ret%)] with an adaptive Bayesian model to set individual upper and lower limits. If values fall outside the individual limits, an athlete may be further targeted and ultimately sanctioned. Since (Hb) varies with plasma volume (PV) fluctuations, possibly caused by training load changes, we investigated the putative influence of acute and chronic training load changes on the ABP variables. Monthly blood samples were collected over one year in 10 male elite cyclists (25.6 ± 3.4 years, 181 ± 4 cm, 71.3 ± 4.9 kg, 6.7 ± 0.8 W.kg-1 5-min maximal power output) to calculate individual ABP profiles and monitor hematological variables. Total hemoglobin mass (Hbmass) and PV were additionally measured by carbon monoxide rebreathing. Acute and chronic training loads-respectively 5 and 42 days before sampling-were calculated considering duration and intensity (training stress score, TSSTM). (Hb) averaged 14.2 ± 0.0 (mean ± SD) g.dL-1 (range: 13.3-15.5 g·dl-1) over the study with significant changes over time (P = 0.004). Hbmass was 1030 ± 87 g (range: 842-1116 g) with no significant variations over time (P = 0.118), whereas PV was 4309 ± 350 mL (range: 3,688-4,751 mL) with a time-effect observed over the study time (P = 0.014). Higher acute-but not chronic-training loads were associated with significantly decreased (Hb) (P <0.001). Although individual hematological variations were observed, all ABP variables remained within the individually calculated limits. Our results support that acute training load variations significantly affect (Hb), likely due to short-term PV fluctuations, underlining the importance of considering training load when interpreting individual ABP variations for anti-doping purposes.


Regulation of the POU domain gene SCIP during cerebral cortical development.
The mammalian cerebral cortex is patterned into layers of neurons that share characteristic morphologies, physiological properties, and axonal connections. Neurons in the various layers are thought to acquire their lamina-specific identities shortly before the time of their final mitosis in the cortical ventricular zone. In order to investigate the molecular basis of laminar patterning in the CNS, we have performed in situ hybridization studies of the POU homeodomain gene SCIP (also known as Tst-1 or Oct-6), which is expressed in proliferating Schwann cells in the PNS and O2A progenitor cells in the developing CNS. In the CNS of adult rats, SCIP is expressed at high levels in the cerebral cortex, specifically in layer 5 pyramidal neurons that form subcortical axonal connections. SCIP is both temporally and spatially regulated during cortical development. Its initial expression in the intermediate zone and cortical plate is correlated with the early migration and differentiation of layer 5 neurons. SCIP hybridization was not, however, observed within the ventricular zone during the period of neurogenesis. SCIP is also expressed at high levels in the neurons of cortical layer 2/3, during their migration and differentiation within the cortical plate. This expression in the upper layers is apparently downregulated during postnatal periods, with the adult pattern apparent by postnatal day 30 (P30). POU domain genes are thought to play a role in cell lineage and cell fate decisions in several systems; thus, SCIP may serve a function in generating discrete laminar phenotypes in the developing cerebral cortex. In addition, since SCIP is a putative repressor of myelin gene expression, our results suggest that SCIP plays a role in regulating transcription in differentiated CNS neurons as well as in proliferating glial precursors.


Elevated early callose deposition results in complete penetration resistance to powdery mildew in Arabidopsis.
A common response by plants to fungal attack is deposition of callose, a (1,3)-β-glucan polymer, in the form of cell wall thickenings called papillae, at site of wall penetration. While it has been generally believed that the papillae provide a structural barrier to slow fungal penetration, this idea has been challenged in recent studies of Arabidopsis (Arabidopsis thaliana), where fungal resistance was found to be independent of callose deposition. To the contrary, we show that callose can strongly support penetration resistance when deposited in elevated amounts at early time points of infection. We generated transgenic Arabidopsis lines that express POWDERY MILDEW RESISTANT4 (PMR4), which encodes a stress-induced callose synthase, under the control of the constitutive 35S promoter. In these lines, we detected callose synthase activity that was four times higher than that in wild-type plants 6 h post inoculation with the virulent powdery mildew Golovinomyces cichoracearum. The callose synthase activity was correlated with enlarged callose deposits and the focal accumulation of green fluorescent protein-tagged PMR4 at sites of attempted fungal penetration. We observed similar results from infection studies with the nonadapted powdery mildew Blumeria graminis f. sp. hordei. Haustoria formation was prevented in resistant transgenic lines during both types of powdery mildew infection, and neither the salicylic acid-dependent nor jasmonate-dependent pathways were induced. We present a schematic model that highlights the differences in callose deposition between the resistant transgenic lines and the susceptible wild-type plants during compatible and incompatible interactions between Arabidopsis and powdery mildew.


The presence of urinary cellular sediment and albuminuria in newspaper pressworkers exposed to solvents.
To investigate the relationship between exposure to organic solvents and the presence of increased urinary cellular sediment, we conducted a cross-sectional study of 215 newspaper pressroom workers who were exposed to solvent and lubricant mixtures. Thirty-two compositors were surveyed as referents. Industrial hygiene measurements showed low-level airborne exposures to organic solvents (primarily naphthas) and minimal airborne exposure to glycol ethers. There was a high prevalence of solvent-related dermatitis indicating there was significant dermal exposure to these substances. Pressworkers were exposed to solvent mixtures that were associated with dose-related increases in leukocyturia alone or in urinary cellular sediment (erythrocyturia and/or leukocyturia). The presence of urinary cellular sediment was associated with increasing frequency of use of five particular organic solvent mixtures. These results suggest that the increase in urinary cellular sediment may be due, at least in part, to the effects of solvents on the kidney. Consistent with this hypothesis, 16% of pressmen and no compositors were found to have primarily low-grade albuminuria detectable by dipstick. Workers with urinary cellular sediment were significantly more likely to have detectable albuminuria. Albuminuria was more likely to occur with increased frequency of use of four particular solvent mixtures. The presence of urinary cellular sediment was less likely to occur with occasional use of analgesics suggesting a possible etiologic role for acute or chronic urinary tract inflammation.


Bioresorbable pressure sensors protected with thermally grown silicon dioxide for the monitoring of chronic diseases and healing processes.
Pressures in the intracranial, intraocular and intravascular spaces are clinically useful for the diagnosis and management of traumatic brain injury, glaucoma and hypertension, respectively. Conventional devices for measuring these pressures require surgical extraction after a relevant operational time frame. Bioresorbable sensors, by contrast, eliminate this requirement, thereby minimizing the risk of infection, decreasing the costs of care and reducing distress and pain for the patient. However, the operational lifetimes of bioresorbable pressure sensors available at present fall short of many clinical needs. Here, we present materials, device structures and fabrication procedures for bioresorbable pressure sensors with lifetimes exceeding those of previous reports by at least tenfold. We demonstrate measurement accuracies that compare favourably to those of the most sophisticated clinical standards for non-resorbable devices by monitoring intracranial pressures in rats for 25 days. Assessments of the biodistribution of the constituent materials, complete blood counts, blood chemistry and magnetic resonance imaging compatibility confirm the biodegradability and clinical utility of the device. Our findings establish routes for the design and fabrication of bioresorbable pressure monitors that meet requirements for clinical use.


Skin-lightening effect of a polyphenol extract from Acerola (Malpighia emarginata DC.) fruit on UV-induced pigmentation.
To investigate the physiological functions of polyphenols from acerola (Malpighia emarginata DC.) fruit, the effects on melanogenesis were studied. The crude polyphenol concentrated extract from acerola (C-AP) was used to examine the skin-lightening effect on brownish guinea pigs which had been subjected to controlled UVB irradiation. The results show that C-AP significantly lightened the UVB-irradiated skin pigmentation. Furthermore, treatment with C-AP reduced the content of melanin in B16 melanoma cells, suggesting that the in vivo skin-lightening effect of C-AP was due to the suppression of melanin biosynthesis in melanocytes. In addition, we found that C-AP could effectively inhibit mushroom tyrosinase activity, the main constituents responsible for this effect being thought to be such anthocyanins as cyanidin-3-alpha-O-rhamnoside (C3R) and pelargonidin-3-alpha-O-rhamnoside (P3R). This result indicates that the skin-lightening effect of C-AP can be partly attributed to the suppression of melanogenesis through the inhibition of tyrosinase activity in melanocytes. An oral ingestion of C-AP may therefore be efficacious for reducing UVB-induced hyper-pigmentation by inhibiting the tyrosinase in melanocytes.


Precision global health and comorbidity: a population-based study of 16 357 people in rural Uganda.
In low-income countries, complex comorbidities and weak health systems confound disease diagnosis and treatment. Yet, data-driven approaches have not been applied to develop better diagnostic strategies or to tailor treatment delivery for individuals within rural poor communities. We observed symptoms/diseases reported within three months by 16 357 individuals aged 1+ years in 17 villages of Mayuge District, Uganda. Symptoms were mapped to the Human Phenotype Ontology. Comorbidity networks were constructed. An edge between two symptoms/diseases was generated if the relative risk greater than 1, ϕ correlation greater than 0, and local false discovery rate less than 0.05. We studied how network structure and flagship symptom profiles varied against biosocial factors. 88.05% of individuals (14 402/16 357) reported at least one symptom/disease. Young children and individuals in worse-off households-low socioeconomic status, poor water, sanitation, and hygiene, and poor medical care-had dense network structures with the highest comorbidity burden and/or were conducive to the onset of new comorbidities from existing flagship symptoms, such as fever. Flagship symptom profiles for fever revealed self-misdiagnoses of fever as malaria and sexually transmitted infections as a potentially missed cause of fever in individuals of reproductive age. Network analysis may inform the development of new diagnostic and treatment strategies for flagship symptoms used to characterize syndromes/diseases of global concern.


From multiplicative noise to directed percolation in wetting transitions.
A simple one-dimensional microscopic model of the depinning transition of an interface from an attractive hard wall is introduced and investigated. Upon varying a control parameter, the critical behavior observed along the transition line changes from a directed-percolation type to a multiplicative-noise type. Numerical simulations allow for a quantitative study of the multicritical point separating the two regions. Mean-field arguments and the mapping on yet a simpler model provide some further insight on the overall scenario.


Does prognosis and socioeconomic status impact on trust in physicians? Interviews with patients with coronary disease in South Australia.
There is concern across a range of healthcare settings worldwide that trust in physicians is declining. Decreased trust may lead to lesser tolerance of prognosis uncertainty and an increased demand for tests, referrals and second opinions. Literature suggests that there has been a recent cultural shift towards decreased trust in, and increased questioning of, medical advice. We investigated the impact of varying prognosis and socioeconomic status (SES) on trust in physicians, and patient questioning of medical advice. Semistructured, audio-recorded transcribed interviews were conducted. The interview schedule was developed with reference to the Health Belief Model. Interviews were conducted between October 2008 and September 2009. Participants were recruited via general practitioner clinics and hospital cardiac rehabilitation programmes. Participants consisted of patients either receiving preventive treatment or active treatment for established cardiovascular disease. A coding structure was developed based on the aim of the research, to investigate the impact of varying prognosis and SES on trust in physicians. Older participants are more likely than their younger counterparts to be unquestioning of medical advice. Higher SES participants are more likely to question medical advice than lower SES participants. Also, unlike primary prevention participants, established pathology increased participants' trust, or decreased questioning behaviour. Participants who perceived themselves at risk of a poor or uncertain outcome were unlikely to doubt medical advice. Blind trust in physicians remains strong in older participants, participants who perceive their prognosis to be uncertain and a proportion of lower SES participants. This is important for practitioners in terms of patient agency and points to the importance of moral and ethical practice. However, physicians also need to be aware that there are a growing proportion of patients for whom trust needs to be developed, and cannot be assumed.


Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion.
Early local tumor invasion in breast cancer results in a likely encounter between cancer cells and mature adipocytes, but the role of these fat cells in tumor progression remains unclear. We show that murine and human tumor cells cocultivated with mature adipocytes exhibit increased invasive capacities in vitro and in vivo, using an original two-dimensional coculture system. Likewise, adipocytes cultivated with cancer cells also exhibit an altered phenotype in terms of delipidation and decreased adipocyte markers associated with the occurrence of an activated state characterized by overexpression of proteases, including matrix metalloproteinase-11, and proinflammatory cytokines [interleukin (IL)-6, IL-1β]. In the case of IL-6, we show that it plays a key role in the acquired proinvasive effect by tumor cells. Equally important, we confirm the presence of these modified adipocytes in human breast tumors by immunohistochemistry and quantitative PCR. Interestingly, the tumors of larger size and/or with lymph nodes involvement exhibit the higher levels of IL-6 in tumor surrounding adipocytes. Collectively, all our data provide in vitro and in vivo evidence that (i) invasive cancer cells dramatically impact surrounding adipocytes; (ii) peritumoral adipocytes exhibit a modified phenotype and specific biological features sufficient to be named cancer-associated adipocytes (CAA); and (iii) CAAs modify the cancer cell characteristics/phenotype leading to a more aggressive behavior. Our results strongly support the innovative concept that adipocytes participate in a highly complex vicious cycle orchestrated by cancer cells to promote tumor progression that might be amplified in obese patients.


Quality of life and patient satisfaction following treatment for menorrhagia.
This prospective cohort study of patients who consulted general practitioners complaining of excessive menstrual bleeding measured changes in quality of life and patients' satisfaction following different forms of treatment for menorrhagia. Three hundred and forty-eight patients were followed-up for 18 months using self-completion questionnaires which included generic measurements of health-related quality of life (SF-36) and a disease-specific questionnaire to measure the social impact of menstrual symptoms. Only 15 patients (4%) received no active treatment, 132 (38%) underwent surgical treatment (hysterectomy or endometrial resection), and the remainder were prescribed drugs. Those in the surgical group with both moderate and severe symptoms experienced significant improvements in their quality of life. Patients with moderate symptoms who did not undergo surgery improved in the social functioning and energy dimensions of the SF-36, but those with severe symptoms who received drug treatment only experienced no significant quality-of-life benefits. Patients who had not had surgery were significantly more likely to be dissatisfied with their treatment (21%) than those in the surgical group (5%). Since menorrhagia can have adverse effects on many aspects of a patient's daily life, it is important to measure the effects of treatment on quality of life. This study has demonstrated the feasibility of doing so.