Pseudogap in the c-axis (along the ladder) optical conductivity of t - J ladders and its quasiparticle interpretation.
Motivated by similarities between cuprate superconductors and two-leg ladder copper-oxide compounds and in order to obtain a better understanding of optical properties of cuprate superconductors we have studied the c-axis (along the ladder) optical conductivity [Formula: see text] of a doped [Formula: see text] two-leg ladder. Using exact diagonalization, we have calculated the conductivity and related quantities for cyclic ladders of up to 13 rungs. In agreement with results of an early study by Hayward and coworkers (Hayward et al 1996 Phys. Rev. B 53 8863) we find that [Formula: see text] consists of a Drude peak at zero frequency and an absorption band in the infrared region that is separated from the former by a pseudogap. The width of the pseudogap [Formula: see text] increases with increasing J/t, in parallel with an increase of the magnitude [Formula: see text] of the gap in the quasiparticle excitation spectra. Our central finding is that [Formula: see text], where [Formula: see text] is the magnitude of the gap in the spin excitation spectra. We demonstrate that this approximate relation can be understood in terms of a phenomenological model involving a superconducting ladder and a coupling between charged quasiparticles and spin excitations. The relation is remarkably similar to the one between experimental values of the energy scale of a dip in the in-plane optical conductivity, the superconducting gap [Formula: see text] and the energy of the spin-resonance in cuprate superconductors (for a recent discussion of the optical data, see Šopík et al 2015 New J. Phys. 17 053022). Our findings support the point of view that low energy infrared active excited states of cuprate superconductors can be viewed as consisting of two charged quasiparticles connected with pair-breaking and a spin excitation.


Improvement of vaginal health for Kenyan women at risk for acquisition of human immunodeficiency virus type 1: results of a randomized trial.
Vaginal infections are common and have been associated with increased risk for acquisition of human immunodeficiency virus type 1 (HIV-1). We conducted a randomized trial of directly observed oral treatment administered monthly to reduce vaginal infections among Kenyan women at risk for HIV-1 acquisition. A trial intervention of 2 g of metronidazole plus 150 mg of fluconazole was compared with metronidazole placebo plus fluconazole placebo. The primary end points were bacterial vaginosis (BV), vaginal candidiasis, trichomoniasis vaginalis (hereafter, "trichomoniasis"), and colonization with Lactobacillus organisms. Of 310 HIV-1-seronegative female sex workers enrolled (155 per arm), 303 were included in the primary end points analysis. A median of 12 follow-up visits per subject were recorded in both study arms (P = .8). Compared with control subjects, women receiving the intervention had fewer episodes of BV (hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.49-0.63) and more frequent vaginal colonization with any Lactobacillus species (HR, 1.47; 95% CI, 1.19-1.80) and H(2)O(2)-producing Lactobacillus species (HR, 1.63; 95% CI, 1.16-2.27). The incidences of vaginal candidiasis (HR, 0.84; 95% CI, 0.67-1.04) and trichomoniasis (HR, 0.55; 95% CI, 0.27-1.12) among treated women were less than those among control subjects, but the differences were not statistically significant. Periodic presumptive treatment reduced the incidence of BV and promoted colonization with normal vaginal flora. Vaginal health interventions have the potential to provide simple, female-controlled approaches for reducing the risk of HIV-1 acquisition.


Why Do People With Schizophrenia Exercise? A Mixed Methods Analysis Among Community Dwelling Regular Exercisers.
Individuals with schizophrenia have reduced rates of physical activity, yet substantial proportions do engage in independent and regular exercise. Previous studies have shown improvement in symptoms and cognitive function in response to supervised exercise programs in people with schizophrenia. There is little data on motivations of individuals who exercise independently, or their chosen type, duration, or setting of exercise. This study explores motivational parameters and subjective experiences associated with sustained, independent exercise in outpatients with a diagnosis of schizophrenia or schizoaffective disorder. Participants completed a semi-structured interview and then were given a prospective survey containing visual analog scales of symptom severity and the Subjective Exercise Experiences Scales to complete immediately before and after three sessions of exercise. Results from the semi-structured interview were analyzed by modified content analysis. The most important reason for exercise was self-image, followed closely by psychological and physical health. Among psychological effects, participants reported exercise was most helpful for mood and cognitive symptoms. The prospective ratings demonstrated 10-15% average improvements in global well-being, energy, and negative, cognitive and mood symptoms, with almost no change in psychosis, after individual exercise sessions. This suggests that non-psychotic parameters are more susceptible to inter-session decay of exercise effects, which may reinforce continued exercise participation.


A Social Media Study on the Effects of Psychiatric Medication Use.
Understanding the effects of psychiatric medications during mental health treatment constitutes an active area of inquiry. While clinical trials help evaluate the effects of these medications, many trials suffer from a lack of generalizability to broader populations. We leverage social media data to examine psychopathological effects subject to self-reported usage of psychiatric medication. Using a list of common approved and regulated psychiatric drugs and a Twitter dataset of 300M posts from 30K individuals, we develop machine learning models to first assess effects relating to mood, cognition, depression, anxiety, psychosis, and suicidal ideation. Then, based on a stratified propensity score based causal analysis, we observe that use of specific drugs are associated with characteristic changes in an individual's psychopathology. We situate these observations in the psychiatry literature, with a deeper analysis of pre-treatment cues that predict treatment outcomes. Our work bears potential to inspire novel clinical investigations and to build tools for digital therapeutics.


Discussing Transgender Topics within Gay-Straight Alliances: Factors that Could Promote More Frequent Conversations.
Gay-Straight Alliances (GSAs) have potential to facilitate conversations on transgender and gender diversity issues among members. We examined how frequently GSA members discussed transgender and gender diversity topics within GSAs, whether GSAs varied from one another in the extent to which these conversations occurred, and identified factors that distinguished which members and GSAs discussed such topics more often than others. Participants were 295 members of 33 high school GSAs in the state of Massachusetts who completed surveys that assessed their experiences within their GSA. On average, youth discussed transgender and gender diversity issues with some regularity, but this varied significantly across GSAs and among youth within each GSA. Youth who had transgender friends, perceived a more respectful GSA climate, and accessed more information/resources and engaged in more advocacy within the GSA reported more frequently discussing transgender and gender diversity issues. Also, GSAs with transgender members, whose members collectively perceived a more respectful climate, accessed more information/resources and did more advocacy, and who reported lower socializing or support discussed transgender and gender diversity issues more frequently than other GSAs. This information could inform GSA programming to facilitate more transgender and gender diversity topic discussions and ensure that members feel encouraged to participate in them.


Tattoo-based potentiometric ion-selective sensors for epidermal pH monitoring.
This article presents the fabrication and characterization of novel tattoo-based solid-contact ion-selective electrodes (ISEs) for non-invasive potentiometric monitoring of epidermal pH levels. The new fabrication approach combines commercially available temporary transfer tattoo paper with conventional screen printing and solid-contact polymer ISE methodologies. The resulting tattoo-based potentiometric sensors exhibit rapid and sensitive response to a wide range of pH changes with no carry-over effects. Furthermore, the tattoo ISE sensors endure repetitive mechanical deformation, which is a key requirement of wearable and epidermal sensors. The flexible and conformal nature of the tattoo sensors enable them to be mounted on nearly any exposed skin surface for real-time pH monitoring of the human perspiration, as illustrated from the response during a strenuous physical activity. The resulting tattoo-based ISE sensors offer considerable promise as wearable potentiometric sensors suitable for diverse applications.


Recent progress in non-native nucleic acid modifications.
While Nature harnesses RNA and DNA to store, read and write genetic information, the inherent programmability, synthetic accessibility and wide functionality of these nucleic acids make them attractive tools for use in a vast array of applications. In medicine, antisense oligonucleotides (ASOs), siRNAs, and therapeutic aptamers are explored as potent targeted treatment and diagnostic modalities, while in the technological field oligonucleotides have found use in new materials, catalysis, and data storage. The use of natural oligonucleotides limits the possible chemical functionality of resulting technologies while inherent shortcomings, such as susceptibility to nuclease degradation, provide obstacles to their application. Modified oligonucleotides, at the level of the nucleobase, sugar and/or phosphate backbone, are widely used to overcome these limitations. This review provides the reader with an overview of non-native modifications and the challenges faced in the design, synthesis, application and outlook of novel modified oligonucleotides.


The role of venous outflow obstruction in patients with chronic venous dysfunction.
To quantify the functional venous outflow obstruction with different location and extent of obstruction attributed to previous deep vein thrombosis. Case-control study. Vascular Laboratory, St Mary's Hospital Medical School, London, England. Two groups: group 1, 25 case patients and 9 control subjects, and group 2, 45 case patients and 30 control subjects. Ascending venography, duplex scanning, air plethysmography, and venous pressure measurements in the foot and the arm via a 21-gauge butterfly needle. Venous outflow fraction (VOF), venous outflow resistance (VOR), and arm-foot pressure differential (A-F PD) at rest and after reactive hyperemia. Venous outflow resistance was evaluated in group 1. Twenty-two case patients underwent VOF testing, and 16 had A-F PD measurement performed. Case patients in group 2 underwent VOF testing. Signs and symptoms of chronic venous dysfunction were associated with the anatomical extent of obstruction. Limb swelling and ache were present in most of the patients; skin changes were noted in about 30% and ulceration in 10% of patients. The results of all tests showed no evidence of obstruction in control subjects. In most case patients with popliteal vein obstruction, test results were similar to those in control subjects: the more proximal the veins involved, the more severe the obstruction. In 16 case patients, all 3 tests were performed and agreement between A-F PD and VOR test results was found in 14 of them. The VOF test results agreed with the results of A-F PD and VOR tests in 9 case patients. In group 2, 50% of the limbs with obstruction proximal to the popliteal vein had a reduced VOF, which became worst in the limbs with extensive obstruction, particularly when the iliac veins were involved. Of the 73 limbs tested for VOF in both groups, only 7 limbs (9.6%) had their venous outflow markedly reduced by occlusion of the superficial veins. The anatomical extent of venous obstruction and the development of collateral circulation determine the hemodynamic severity of the chronic venous obstruction. The deep collaterals seem to be more important than the superficial venous system in bypassing the obstruction. The VOR and the A-F PD tests can be used to identify those patients who have venous obstruction, whereas the use of the VOF test may reduce the need for performing the above tests in 50% of the patients.


Comparative marker analysis of extracellular vesicles in different human cancer types.
Several cell types, including tumour cells, secrete extracellular vesicles (EVs), and tumour-derived EVs play a role in cancer initiation and progression. These vesicles include both a common set of membrane and cytosolic proteins and origin-specific subsets of proteins that likely correlated to cell type-associated functions. To confirm the presence of EVs in the preparations, researchers have identified so-called EV marker proteins, including the tetraspanin family proteins and such cytosolic proteins as heat shock 70 kDa protein 4 (HSP70) and tumour susceptibility gene 101 (TSG101). However, studies have shown that some EV markers are not always present in all EVs, which not only complicates the identification of EVs but also precludes the quantitative evaluation of EV proteins. Thus, it is strongly required to explore well-conserved EV marker proteins that are present at similar levels, regardless of their tissue or cellular origin. In this study, we compared the presence of 11 well-known EV marker proteins by immunoblotting using EVs isolated from 4 human prostate cell lines and 5 human breast cell lines, including cancer cells with different phenotypes. We found that all the tested EVs were positive for CD9 and CD81, with similar abundance that was irrespective of the EV origin. In contrast, other EV marker proteins, such as TSG101, Rab-5b and CD63, were detected in an inconsistent manner, depending on the origin of the EVs. Thus, we propose that the detection of CD9 and/or CD81 should ensure the presence of EVs.


Aluminium phosphide poisoning: a case report.
This paper reports the case of a family in which three children were presented at Emergency Room (ER) with poisoning after the use of a pesticide at home. Initially, the cases were managed as routine cases of organophosphorus poisoning; however, the death of two children made the health team members realise that the poison's effects were delayed and devastating. Later, the compound was identified as Aluminium Phosphide (ALP), and the life of the last surviving child in the family was saved.


[Arsenic contents in soil, water, and crops in an e-waste disposal area].
In order to study whether disposing electronic wastes and secondary metal smelting could cause an arsenic pollution in the environment or not, Luqiao town, Taizhou City, Zhejiang Province was selected as a study area. The main purpose of this paper was to characterize arsenic contents in the local environment, including waters, sediments, soils and rice, and to assess the potential risk to humans. Additionally, the arsenic spatial distribution property and arsenic uptake-translocation rule in soil-rice system were also studied. The results showed that the average arsenic levels in the surface water and the groundwater were 8.26 microg/L and 18.52 microg/L, respectively, which did not exceed the limiting value of Chinese Environment Standards class III . Whereas,some groundwater exceeded the recommended standard by the WHO for drinking water (10 microg/L). The arsenic (on average 7.11 mg/kg) in paddy soils and arsenic (on average 6.17 mg/kg) in the vegetable garden soils were lower than the value recommended by the National Standard (level I). The average arsenic contents in brown rice and husks were 165.1 microg/kg and 144.2 microg/kg, which was also lower than the Chinese Foods Quality Standard. The arsenic contents between the corresponding soils-rice and husks-brown rice showed significantly positive correlations. By comparison, the arsenic contents of soils and husks collected around electroplating were relatively higher than most of other pollutant sources, indicating the electroplating may lead accumulation of arsenic in the paddy soil-rice system.


Mapping vibrational surface and bulk modes in a single nanocube.
Imaging of vibrational excitations in and near nanostructures is essential for developing low-loss infrared nanophotonics, controlling heat transport in thermal nanodevices, inventing new thermoelectric materials and understanding nanoscale energy transport. Spatially resolved electron energy loss spectroscopy has previously been used to image plasmonic behaviour in nanostructures in an electron microscope, but hitherto it has not been possible to map vibrational modes directly in a single nanostructure, limiting our understanding of phonon coupling with photons and plasmons. Here we present spatial mapping of optical and acoustic, bulk and surface vibrational modes in magnesium oxide nanocubes using an atom-wide electron beam. We find that the energy and the symmetry of the surface polariton phonon modes depend on the size of the nanocubes, and that they are localized to the surfaces of the nanocube. We also observe a limiting of bulk phonon scattering in the presence of surface phonon modes. Most phonon spectroscopies are selectively sensitive to either surface or bulk excitations; therefore, by demonstrating the excitation of both bulk and surface vibrational modes using a single probe, our work represents advances in the detection and visualization of spatially confined surface and bulk phonons in nanostructures.


Effect of renal function on pemetrexed-induced haematotoxicity.
Pemetrexed (PEM) is an anticancer agent used for the treatment of non-small cell lung cancer, malignant pleural mesothelioma and thymoma. Reportedly, PEM has higher efficacy and safety when used in combination with platinum-based agents. However, there are only few reports on the safety of PEM in patients with an eGFR of ≤45 mL/min. We examined the effect of renal function on the safety of regimens containing PEM. We retrospectively reviewed 221 patients with lung cancer, malignant pleural mesothelioma or thymoma who received treatment with a PEM-containing regimen between 2009 and 2014. Subgroup analyses were performed on the basis of pre-treatment renal function: group A [creatinine clearance (CLcr), <45 mL/min]; group B (CLcr, 45-80 mL/min); and group C (CLcr, ≥80 mL/min). For the purpose of this analysis, the lowest documented blood cell counts and haemoglobin levels, the highest levels of serum creatinine, aspartate aminotransferase, alanine aminotransferase and CLcr from the time of initial administration up to prior to the start of second administration were considered. Groups A, B and C had 8, 123 and 90 patients, respectively. The incidence of grade 2 thrombocytopaenia was significantly higher in group A as compared to that in groups B (P < 0.01) and C (P < 0.05). On multivariate analysis, only a CLcr of <45 mL/min was an independent risk factor for thrombocytopaenia of ≥grade 2. When administering a PEM-containing regimen, thrombocytopaenia of ≥grade 2 is more likely to develop in patients with a CLcr of <45 mL/min.


The menacing phantom: what pulls the trigger?
Phantom phenomena are frequent following amputation, but how this often painful experience is modified or triggered by spontaneous events or sensations often puzzles amputees and clinicians alike. We explored triggers of phantom phenomena in a heterogeneous sample of 264 upper and lower limb adult amputees with phantom sensations. Participants completed a structured questionnaire to determine the prevalence and nature of the triggers of phantom phenomena. The four categories of triggers identified include: (a) a quarter of participants experiencing psychological, emotional or autonomic triggers; (b) half experiencing behavioral triggers, "forgetting" the limb's absence and attempting to use the phantom; (c) one-fifth experiencing weather-induced triggers; and (d) one-third experiencing sensations referred from parts of the body. Upper limb amputees; and were more likely to experience weather-induced phantom phenomena than lower limb amputees; and upper and lower limb amputees were equally likely to experience referred sensations from the genitals, contradicting the homuncular remapping hypothesis. Traumatic amputees were more likely to report emotional triggers. Further, while those with emotional triggers exhibited poorer acceptance of the limitations of amputation, they were more likely to employ adaptive coping mechanisms. Finally, habitual "forgetting" behaviors were most common soon after amputation, whereas other more adaptive schemata (e.g., self-defense) were equally likely to be performed at any time following amputation. Various likely inter-related mechanisms are discussed in relation to phantom triggers. Ultimately, optimizing stump and neuroma management, as well as restoring function of central networks for pain, limb movement, and amputation-related memories, should help manage spontaneously triggered phantom phenomena.


Descriptive Analysis of Venous Thromboembolism in Georgia Trauma Centers Compared with National Trauma Centers Participating in the Trauma Quality Improvement Program.
This study was designed to compare the incidence of venous thromboembolism (VTE) in Georgia trauma centers with other national trauma centers participating in the Trauma Quality Improvement Program (TQIP). The use of chemoprophylaxis and characteristics of patients who developed VTE were also examined. We conducted a retrospective observational study of 325,703 trauma admissions to 245 trauma centers from 2013 to 2014. Patient demographics, rate of VTE, as well as the use, type, and timing of chemoprophylaxis were compared between patients admitted to Georgia and non-Georgia trauma centers. The rate of VTE in Georgia trauma centers was 1.9 per cent compared with 2.1 per cent in other national trauma centers. Overall, 49.6 per cent of Georgia patients and 45.5 per cent of patients in other trauma centers had documented chemoprophylaxis. Low molecular weight heparin was the most commonly used medication. Most patients who developed VTE did so despite receiving prophylaxis. The rate of VTE despite prophylaxis was 3.2 per cent in Georgia and 3.1 per cent in non-Georgia trauma centers. Mortality associated with VTE was higher in Georgia trauma centers compared with national TQIP benchmarks. The incidence of VTE and use of chemoprophylaxis within Georgia trauma centers were similar to national TQIP data. Interestingly, most patients who developed VTE in both populations received VTE prophylaxis. Further research is needed to develop best-practice guidelines for prevention, early detection, and treatment in high-risk populations.


Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells.
Interleukin 17 (IL-17)-producing CD4(+) helper T cells (T(H)-17 cells) have been linked to host defense and autoimmune diseases. In mice, the differentiation of T(H)-17 cells requires transforming growth factor-beta and IL-6 and the transcription factor RORgammat. We report here that for human naive CD4(+) T cells, RORgammat expression and T(H)-17 polarization were induced by IL-1beta and enhanced by IL-6 but were suppressed by transforming growth factor-beta and IL-12. Monocytes and conventional dendritic cells, but not monocyte-derived dendritic cells activated by microbial stimuli, efficiently induced T(H)-17 priming, and this function correlated with antigen-presenting cell production of IL-1beta and IL-6 but not IL-12. Our results identify cytokines, antigen-presenting cells and microbial products that promote the polarization of human T(H)-17 cells and emphasize an important difference in the requirements for the differentiation of T(H)-17 cells in humans and mice.


Emotionotopy in the human right temporo-parietal cortex.
Humans use emotions to decipher complex cascades of internal events. However, which mechanisms link descriptions of affective states to brain activity is unclear, with evidence supporting either local or distributed processing. A biologically favorable alternative is provided by the notion of gradient, which postulates the isomorphism between functional representations of stimulus features and cortical distance. Here, we use fMRI activity evoked by an emotionally charged movie and continuous ratings of the perceived emotion intensity to reveal the topographic organization of affective states. Results show that three orthogonal and spatially overlapping gradients encode the polarity, complexity and intensity of emotional experiences in right temporo-parietal territories. The spatial arrangement of these gradients allows the brain to map a variety of affective states within a single patch of cortex. As this organization resembles how sensory regions represent psychophysical properties (e.g., retinotopy), we propose emotionotopy as a principle of emotion coding.


Spirometer-triggered high-resolution computed tomography and pulmonary function measurements during an acute exacerbation in patients with cystic fibrosis.
To evaluate a high-resolution computed tomography (HRCT) scoring system, clinical parameters, and pulmonary function measurements in patients with cystic fibrosis (CF) before and after therapy for a pulmonary exacerbation. Patients (n = 17) were evaluated by spirometer-triggered HRCT imaging, clinical parameters, and pulmonary function tests (PFTs) before and after treatment. HRCT scans were reviewed by 3 radiologists using a modified Bhalla scoring system. Bronchiectasis, bronchial wall thickening, and air trapping were identified in all subjects on initial evaluation. The initial total HRCT score correlated significantly with the Brasfield score (r = -.91, P <.001) and several PFT measures. After treatment, there were improvements in the acute change clinical score (ACCS) (P <.001), most pulmonary function measurements, and total HRCT score (P <.05). Bronchiectasis, bronchial wall thickening, and air trapping did not significantly change. Mucus plugging subcomponent HRCT score, slow vital capacity (SVC), forced expiratory volume in 1 second (FEV(1)), and forced vital capacity (FVC) (percent predicted) and reversible and total HRCT scores were most sensitive to change by effect size analysis. Improvements occurred with treatment in total and reversible HRCT scores, PFTs, and ACCS. Total and reversible HRCT scores and percent predicted SVC, FEV1, and FVC were the most sensitive to change. The greatest change was seen in the mucus plugging subcomponent HRCT score.


Television watching and other sedentary behaviors in relation to risk of obesity and type 2 diabetes mellitus in women.
Current public health campaigns to reduce obesity and type 2 diabetes have largely focused on increasing exercise, but have paid little attention to the reduction of sedentary behaviors. To examine the relationship between various sedentary behaviors, especially prolonged television (TV) watching, and risk of obesity and type 2 diabetes in women. Prospective cohort study conducted from 1992 to 1998 among women from 11 states in the Nurses' Health Study. The obesity analysis included 50 277 women who had a body mass index (BMI) of less than 30 and were free from diagnosed cardiovascular disease, diabetes, or cancer and completed questions on physical activity and sedentary behaviors at baseline. The diabetes analysis included 68 497 women who at baseline were free from diagnosed diabetes mellitus, cardiovascular disease, or cancer. Onset of obesity and type 2 diabetes mellitus. During 6 years of follow-up, 3757 (7.5%) of 50 277 women who had a BMI of less than 30 in 1992 became obese (BMI > or =30). Overall, we documented 1515 new cases of type 2 diabetes. Time spent watching TV was positively associated with risk of obesity and type 2 diabetes. In the multivariate analyses adjusting for age, smoking, exercise levels, dietary factors, and other covariates, each 2-h/d increment in TV watching was associated with a 23% (95% confidence interval [CI], 17%-30%) increase in obesity and a 14% (95% CI, 5%-23%) increase in risk of diabetes; each 2-h/d increment in sitting at work was associated with a 5% (95% CI, 0%-10%) increase in obesity and a 7% (95% CI, 0%-16%) increase in diabetes. In contrast, standing or walking around at home (2 h/d) was associated with a 9% (95% CI, 6%-12%) reduction in obesity and a 12% (95% CI, 7%-16%) reduction in diabetes. Each 1 hour per day of brisk walking was associated with a 24% (95% CI, 19%-29%) reduction in obesity and a 34% (95% CI, 27%-41%) reduction in diabetes. We estimated that in our cohort, 30% (95% CI, 24%-36%) of new cases of obesity and 43% (95% CI, 32%-52%) of new cases of diabetes could be prevented by adopting a relatively active lifestyle (<10 h/wk of TV watching and > or =30 min/d of brisk walking). Independent of exercise levels, sedentary behaviors, especially TV watching, were associated with significantly elevated risk of obesity and type 2 diabetes, whereas even light to moderate activity was associated with substantially lower risk. This study emphasizes the importance of reducing prolonged TV watching and other sedentary behaviors for preventing obesity and diabetes.


Multiple CaMKII Binding Modes to the Actin Cytoskeleton Revealed by Single-Molecule Imaging.
Localization of the Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) to dendritic spine synapses is determined in part by the actin cytoskeleton. We determined binding of GFP-tagged CaMKII to tag-RFP-labeled actin cytoskeleton within live cells using total internal reflection fluorescence microscopy and single-molecule tracking. Stepwise photobleaching showed that CaMKII formed oligomeric complexes. Photoactivation experiments demonstrated that diffusion out of the evanescent field determined the track lifetimes. Latrunculin treatment triggered a coupled loss of actin stress fibers and the colocalized, long-lived CaMKII tracks. The CaMKIIα (α) isoform, which was previously thought to lack F-actin interactions, also showed binding, but this was threefold weaker than that observed for CaMKIIβ (β). The βE' splice variant bound more weakly than α, showing that binding by β depends critically on the interdomain linker. The mutations βT287D and αT286D, which mimic autophosphorylation states, also abolished F-actin binding. Autophosphorylation triggers autonomous CaMKII activity, but does not impair GluN2B binding, another important synaptic protein interaction of CaMKII. The CaMKII inhibitor tatCN21 or CaMKII mutations that inhibit GluN2B association by blocking binding of ATP (βK43R and αK42M) or Ca(2+)/calmodulin (βA303R) had no effect on the interaction with F-actin. These results provide the first rationale for the reduced synaptic spine localization of the αT286D mutant, indicating that transient F-actin binding contributes to the synaptic localization of the CaMKIIα isoform. The track lifetime distributions had a stretched exponential form consistent with a heterogeneously diffusing population. This heterogeneity suggests that CaMKII adopts different F-actin binding modes, which is most easily rationalized by multiple subunit contacts between the CaMKII dodecamer and the F-actin cytoskeleton that stabilize the initial weak (micromolar) monovalent interaction.


RNA-seq of HaHV-1-infected abalones reveals a common transcriptional signature of Malacoherpesviruses.
Haliotid herpesvirus-1 (HaHV-1) is the viral agent causative of abalone viral ganglioneuritis, a disease that has severely affected gastropod aquaculture. Although limited, the sequence similarity between HaHV-1 and Ostreid herpesvirus-1 supported the assignment of both viruses to Malacoherpesviridae, a Herpesvirales family distantly related with other viruses. In this study, we reported the first transcriptional data of HaHV-1, obtained from an experimental infection of Haliotis diversicolor supertexta. We also sequenced the genome draft of the Chinese HaHV-1 variant isolated in 2003 (HaHV-1-CN2003) by PacBio technology. Analysis of 13 million reads obtained from 3 RNA samples at 60 hours post injection (hpi) allowed the prediction of 51 new ORFs for a total of 117 viral genes and the identification of 207 variations from the reference genome, consisting in 135 Single Nucleotide Polymorphisms (SNPs) and 72 Insertions or Deletions (InDels). The pairing of genomic and transcriptomic data supported the identification of 60 additional SNPs, representing viral transcriptional variability and preferentially grouped in hotspots. The expression analysis of HaHV-1 ORFs revealed one putative secreted protein, two putative capsid proteins and a possible viral capsid protease as the most expressed genes and demonstrated highly synchronized viral expression patterns of the 3 infected animals at 60 hpi. Quantitative reverse transcription data of 37 viral genes supported the burst of viral transcription at 30 and 60 hpi during the 72 hours of the infection experiment, and allowed the distinction between early and late viral genes.


Biodegradation of decabromodiphenyl ether (BDE 209) by a newly isolated bacterium from an e-waste recycling area.
Polybrominated diphenyl ethers (PBDEs) have become widespread environmental pollutants all over the world. A newly isolated bacterium from an e-waste recycling area, Stenotrophomonas sp. strain WZN-1, can degrade decabromodiphenyl ether (BDE 209) effectively under aerobic conditions. Orthogonal test results showed that the optimum conditions for BDE 209 biodegradation were pH 5, 25 °C, 0.5% salinity, 150 mL minimal salt medium volume. Under the optimized condition, strain WZN-1 could degrade 55.15% of 65 μg/L BDE 209 under aerobic condition within 30 day incubation. Moreover, BDE 209 degradation kinetics was fitted to a first-order kinetics model. The biodegradation mechanism of BDE 209 by strain WZN-1 were supposed to be three possible metabolic pathways: debromination, hydroxylation, and ring opening processes. Four BDE 209 degradation genes, including one hydrolase, one dioxygenase and two dehalogenases, were identified based on the complete genome sequencing of strain WZN-1. The real-time qPCR demonstrated that the expression level of four identified genes were significantly induced by BDE 209, and they played an important role in the degradation process. This study is the first to demonstrate that the newly isolated Stenotrophomonas strain has an efficient BDE 209 degradation ability and would provide new insights for the microbial degradation of PBDEs.


Exclusive and common targets of neostriatofugal projections of rat striosome neurons: a single neuron-tracing study using a viral vector.
The rat neostriatum has a mosaic organization composed of striosome/patch compartments embedded in a more extensive matrix compartment, which are distinguished from each other by the input-output organization as well as by the expression of many molecular markers. The matrix compartment gives rise to the dual γ-aminobutyric acid (GABA)ergic striatofugal systems, i.e. direct and indirect pathway neurons, whereas the striosome compartment is considered to involve direct pathway neurons alone. Although the whole axonal arborization of matrix striatofugal neurons has been examined in vivo by intracellular staining, that of striosome neurons has never been studied at the single neuron level. In the present study, the axonal arborizations of single striosome projection neurons in rat neostriatum were visualized in their entirety using a viral vector expressing membrane-targeted green fluorescent protein, and compared with that of matrix projection neurons. We found that not only matrix but also striosome compartments contained direct and indirect pathway neurons. Furthermore, only striatonigral neurons in the striosome compartment projected directly to the substantia nigra pars compacta (SNc), although they sent a substantial number of axon collaterals to the globus pallidus, entopeduncular nucleus and/or substantia nigra pars reticulata. These results suggest that striosome neurons play a more important role in the formation of reward-related signals of SNc dopaminergic neurons than do matrix neurons. Together with data from previous studies in the reinforcement learning theory, our results suggest that these direct and indirect striosome-SNc pathways together with nigrostriatal dopaminergic neurons may help striosome neurons to acquire the state-value function.


The relationship between bone turnover markers and BMD decreasing rates in Chinese middle-aged women.
The relationship between bone turnover markers (BTMs) and BMD decreasing rate (BDR) in Chinese women is unclear. Wu investigated the relationship between (BTMs) and BDR at various skeletal sites in Chinese middle-aged women. A cross-section study of 555 healthy Chinese women over 35-60years of age. BMD at posteroanterior spine, the left hip, and the left forearm were measured with a DXA. Levels of serum osteocalcin (OC), bone-specific alkaline phosphatase (BAP), cross-linked N-terminal telopeptides of type I collagen (sNTX) and total urinary deoxypyridinoline (uDPD) were determined. BDR at various skeletal sites had significant negative correlation with serum OC(r=-0.395 to -0.530), BAP(r=-0.297 to -0.486), and sNTX(r=-0.207 to -0.272). After adjustment of age and weight, serum OC, BAP, and sNTX rather than total uDPD still exhibited significant correlations with BDR. Stepwise regression analyses showed that, serum OC and BAP were the significantly negative determinants of BDR. Between 4.7-27.7% and 1.2-16.1% of the changes in BDR were determined by serum OC and BAP, respectively. However, sNTX and total uDPD had no significant effect on BDR at various skeletal sites. This study indicated the correlation between BTMs and early-stage BDR in Chinese middle-aged women and suggested that serum OC and BAP, rather than sNTX and total uDPD, are the key determining factors of early BMD decreases.


Predicting the effects of human developments on individual dolphins to understand potential long-term population consequences.
Human activities that impact wildlife do not necessarily remove individuals from populations. They may also change individual behaviour in ways that have sublethal effects. This has driven interest in developing analytical tools that predict the population consequences of short-term behavioural responses. In this study, we incorporate empirical information on the ecology of a population of bottlenose dolphins into an individual-based model that predicts how individuals' behavioural dynamics arise from their underlying motivational states, as well as their interaction with boat traffic and dredging activities. We simulate the potential effects of proposed coastal developments on this population and predict that the operational phase may affect animals' motivational states. For such results to be relevant for management, the effects on individuals' vital rates also need to be quantified. We investigate whether the relationship between an individual's exposure and the survival of its calves can be directly estimated using a Bayesian multi-stage model for calf survival. The results suggest that any effect on calf survival is probably small and that a significant relationship could only be detected in large, closely studied populations. Our work can be used to guide management decisions, accelerate the consenting process for coastal and offshore developments and design targeted monitoring.


Automated Ecological Assessment of Physical Activity: Advancing Direct Observation.
Technological advances provide opportunities for automating direct observations of physical activity, which allow for continuous monitoring and feedback. This pilot study evaluated the initial validity of computer vision algorithms for ecological assessment of physical activity. The sample comprised 6630 seconds per camera (three cameras in total) of video capturing up to nine participants engaged in sitting, standing, walking, and jogging in an open outdoor space while wearing accelerometers. Computer vision algorithms were developed to assess the number and proportion of people in sedentary, light, moderate, and vigorous activity, and group-based metabolic equivalents of tasks (MET)-minutes. Means and standard deviations (SD) of bias/difference values, and intraclass correlation coefficients (ICC) assessed the criterion validity compared to accelerometry separately for each camera. The number and proportion of participants sedentary and in moderate-to-vigorous physical activity (MVPA) had small biases (within 20% of the criterion mean) and the ICCs were excellent (0.82-0.98). Total MET-minutes were slightly underestimated by 9.3-17.1% and the ICCs were good (0.68-0.79). The standard deviations of the bias estimates were moderate-to-large relative to the means. The computer vision algorithms appeared to have acceptable sample-level validity (i.e., across a sample of time intervals) and are promising for automated ecological assessment of activity in open outdoor settings, but further development and testing is needed before such tools can be used in a diverse range of settings.


A randomised trial comparing spatio-temporal gait parameters after total hip arthroplasty between the direct anterior and direct lateral surgical approaches.
Total hip arthroplasty (THA) is a successful procedure for relieving symptoms of severe osteoarthritis. Surgical approach is a key factor in early recovery and although controversial, little has been written about the direct anterior (DA) approach using objective early measures. 78 participants were prospectively enrolled to undergo a THA through either a DA or direct lateral (DL) surgical approach. Outcome measures were collected preoperatively and at discharge from the hospital, and 2-, 6- and 12-weeks. Outcome measures included the GAITRite® system to measure gait velocity, stride length, single-limb support and single-limb support symmetry. At each time point participants also completed the Timed Up and Go (TUG), the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), 12-Item Short-Form Survey (SF-12), Harris Hip Score, and pain visual analog scale (VAS). We found statistically significant differences in gait velocity at discharge, 2-weeks and 6-weeks in favour of the DA group (all p < 0.01). We also found significant differences in favour of the DA group for single-limb support symmetry at 6-weeks ( p < 0.01) and 12-weeks ( p < 0.01). The time to complete the TUG test was also significantly shorter in the DA group at 2-weeks ( p < 0.01) and 6-weeks ( p < 0.01) compared to the DL group. However, there were no statistically significant differences in any of the patient-reported outcomes. The DA surgical approach was found to offer significant early advantages in function compared to the DL group, with no differences in quality of life or pain.


Residual macrovascular risk in 2013: what have we learned?
Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.


Nuclear import of UBL-domain protein Mdy2 is required for heat-induced stress response in Saccharomyces cerevisiae.
Ubiquitin (Ub) and ubiquitin-like (UBL) proteins regulate a diverse array of cellular pathways through covalent as well as non-covalent interactions with target proteins. Yeast protein Mdy2 (Get5) and its human homolog GdX (Ubl4a) belong to the class of UBL proteins which do not form conjugates with other proteins. Mdy2 is required for cell survival under heat stress and for efficient mating. As part of a complex with Sgt2 and Get4 it has been implicated in the biogenesis of tail-anchored proteins. Interestingly, in response to heat stress, Mdy2 protein that is predominantly localized in the nucleus co-localized with poly(A)-binding protein Pab1 to cytoplasmic stress granules suggesting that nucleocytoplasmic shuttling is of functional importance. Here we investigate the nuclear import of Mdy2, a process that is independent of the Get4/Sgt2 complex but required for stress response. Nuclear import is mediated by an N-terminal nuclear localization signal (NLS) and this process is essential for the heat stress response. In contrast, cells expressing Mdy2 lacking a nuclear export signal (NES) behave like wild type. Importantly, both Mdy2 and Mdy2-ΔNES, but not Mdy2-ΔNLS, physically interact with Pab1 and this interaction correlates with the accumulation in cytoplasmic stress granules. Thus, the nuclear history of the UBL Mdy2 appears to be essential for its function in cytoplasmic stress granules during the rapid cellular response to heat stress.


PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study.
Statin treatment and variants in the gene encoding HMG-CoA reductase are associated with reductions in both the concentration of LDL cholesterol and the risk of coronary heart disease, but also with modest hyperglycaemia, increased bodyweight, and modestly increased risk of type 2 diabetes, which in no way offsets their substantial benefits. We sought to investigate the associations of LDL cholesterol-lowering PCSK9 variants with type 2 diabetes and related biomarkers to gauge the likely effects of PCSK9 inhibitors on diabetes risk. In this mendelian randomisation study, we used data from cohort studies, randomised controlled trials, case control studies, and genetic consortia to estimate associations of PCSK9 genetic variants with LDL cholesterol, fasting blood glucose, HbA1c, fasting insulin, bodyweight, waist-to-hip ratio, BMI, and risk of type 2 diabetes, using a standardised analysis plan, meta-analyses, and weighted gene-centric scores. Data were available for more than 550 000 individuals and 51 623 cases of type 2 diabetes. Combined analyses of four independent PCSK9 variants (rs11583680, rs11591147, rs2479409, and rs11206510) scaled to 1 mmol/L lower LDL cholesterol showed associations with increased fasting glucose (0·09 mmol/L, 95% CI 0·02 to 0·15), bodyweight (1·03 kg, 0·24 to 1·82), waist-to-hip ratio (0·006, 0·003 to 0·010), and an odds ratio for type diabetes of 1·29 (1·11 to 1·50). Based on the collected data, we did not identify associations with HbA1c (0·03%, -0·01 to 0·08), fasting insulin (0·00%, -0·06 to 0·07), and BMI (0·11 kg/m2, -0·09 to 0·30). PCSK9 variants associated with lower LDL cholesterol were also associated with circulating higher fasting glucose concentration, bodyweight, and waist-to-hip ratio, and an increased risk of type 2 diabetes. In trials of PCSK9 inhibitor drugs, investigators should carefully assess these safety outcomes and quantify the risks and benefits of PCSK9 inhibitor treatment, as was previously done for statins. British Heart Foundation, and University College London Hospitals NHS Foundation Trust (UCLH) National Institute for Health Research (NIHR) Biomedical Research Centre.


Control of aggregation temperatures in mixed and blended cytocompatible thermoresponsive block co-polymer nanoparticles.
A small library of thermoresponsive amphiphilic copolymers based on polylactide-block-poly((2-(2-methoxyethoxy)ethyl methacrylate)-co-(oligoethylene glycol methacrylate)) (PLA-b-P(DEGMA)-co-(OEGMA)), was synthesised by copper-mediated controlled radical polymerisation (CRP) with increasing ratios of OEGMA : DEGMA. These polymers were combined in two ways to form nanoparticles with controllable thermal transition temperatures as measured by particle aggregation. The first technique involved the blending of two (PLA-b-P(DEGMA)-co-(OEGMA)) polymers together prior to assembling nanoparticles (NPs). The second method involved mixing pre-formed nanoparticles of single (PLA-b-P(DEGMA)-co-(OEGMA)) polymers. The observed critical aggregation temperature Tt did not change in a linear relationship with the ratios of each copolymer either in the nanoparticles blended from different copolymers or in the mixtures of pre-formed nanoparticles. However, where co-polymer mixtures were based on (OEG)9MA ratios within 5-10 mole%, a linear relationship between (OEG)9MA composition in the blends and Tt was obtained. The data suggest that OEGMA-based copolymers are tunable over a wide temperature range given suitable co-monomer content in the linear polymers or nanoparticles. Moreover, the thermal transitions of the nanoparticles were reversible and repeatable, with the cloud point curves being essentially invariant across at least three heating and cooling cycles, and a selected nanoparticle formulation was found to be readily endocytosed in representative cancer cells and fibroblasts.


Fetal abdominal circumference in the second trimester and prediction of small for gestational age at birth.
Background: Infants that are small for gestational age (SGA) at birth are at increased risk for morbidity and mortality. Unfortunately, the antenatal prediction of SGA is suboptimal.Objectives: We sought to: (1) examine the association between second trimester fetal abdominal circumference < 10% (2T-AClag) with SGA and other gestational and neonatal adverse outcomes; (2) assess 2T-AClag as a predictor of SGA.Study design: Retrospective study of 212 singleton gestations with 2T-AClag on routine ultrasound between 18-24 weeks. The study group was compared to 424 gestations without 2T-AClag for maternal characteristics as well as pregnancy and neonatal adverse outcomes. A multivariate logistic regression was used to determine the predictive value of 2T-AClag for SGA, adjusting for maternal and pregnancy characteristics. The screening model accuracy was assessed through receiver operating characteristic (ROC) curves. Fetal growth restriction (FGR) was defined as an estimated fetal weight (EFW) less than the 10th percentile.Results: Gestations with 2T-AClag had higher rates of SGA (35.7 versus 11.6%, p < .0001), FGR (17 versus 1.7%, p < .0001), pregnancy induced hypertension (31.1 versus 17%, p < .0001), preeclampsia (14.6 versus 7.8%, 0 = 0.01), abnormal umbilical artery Doppler (30 versus 5.1%, p < .0001), indicated preterm birth (5.7 versus 1.9%, p = .01), primary cesarean birth (29.6 versus 20.1%, p = .01) and NICU admission (12.9 versus 6.4%, p = .009). After adjusting for maternal and gestational risk factors, 2T-AClag remained an independent risk factor for SGA (OR 4.53, 95%CI 2.91-7.05, p < .0001) and FGR (OR 11.57, 95%CI 5.02-26.65, p < .0001). The inclusion of 2T-AClag in a regression model with traditional risk factors, significantly improved the model's predictability for SGA and FGR (area under ROC curve increased from 0.618 to 0.723 and 0.653 to 0.819, respectively, p < .0001).Conclusions: Second trimester abdominal circumference (AC) lag is associated with an increased risk of SGA, FGR and other adverse outcomes. The inclusion of 2T-AClag in a screening model for prediction of SGA and FGR may improve the identification of this at-risk group and assist in customizing surveillance plans.Brief rationaleScreening for newborns that are small for gestational age (SGA) at birth is currently suboptimal. Our study shows that second trimester abdominal circumference (AC) lag, using a parameter already routinely assessed during anatomic survey, is associated with SGA at birth and can improve current screening for growth restriction and other gestational, fetal and neonatal complications.


Asymmetric Supercapacitors Using 3D Nanoporous Carbon and Cobalt Oxide Electrodes Synthesized from a Single Metal-Organic Framework.
Nanoporous carbon and nanoporous cobalt oxide (Co3O4) materials have been selectively prepared from a single metal-organic framework (MOF) (zeolitic imidazolate framework, ZIF-67) by optimizing the annealing conditions. The resulting ZIF-derived carbon possesses highly graphitic walls and a high specific surface area of 350 m(2)·g(-1), while the resulting ZIF-derived nanoporous Co3O4 possesses a high specific surface area of 148 m(2)·g(-1) with much less carbon content (1.7 at%). When nanoporous carbon and nanoporous Co3O4 were tested as electrode materials for supercapacitor application, they showed high capacitance values (272 and 504 F·g(-1), respectively, at a scan rate of 5 mV·s(-1)). To further demonstrate the advantages of our ZIF-derived nanoporous materials, symmetric (SSCs) and asymmetric supercapacitors (ASCs) were also fabricated using nanoporous carbon and nanoporous Co3O4 electrodes. Improved capacitance performance was successfully realized for the ASC (Co3O4//carbon), better than those of the SSCs based on nanoporous carbon and nanoporous Co3O4 materials (i.e., carbon//carbon and Co3O4//Co3O4). The developed ASC with an optimal mass loading can be operated within a wide potential window of 0.0-1.6 V, which leads to a high specific energy of 36 W·h·kg(-1). More interestingly, this ASC also exhibits excellent rate capability (with the highest specific power of 8000 W·kg(-1) at a specific energy of 15 W·h·kg(-1)) combined with long-term stability up to 2000 cycles.


Phellinus linteus Extract Exerts Anti-asthmatic Effects by Suppressing NF-κB and p38 MAPK Activity in an OVA-induced Mouse Model of Asthma.
Phellinus linteus has been used as a traditional herbal medicine in Asian countries and is known to have anti-tumor, immunomodulatory, anti-inflammatory, and anti-allergic activities. However, the protective effects of P. linteus against experimental asthma have not been fully investigated. The objective of this study was to determine whether P. linteus ethanol extract (PLE) suppresses inflammatory response in an OVA-induced asthma model. As expected, the oral administration of PLE significantly inhibited eosinophilic airway inflammation and airway hyperresponsiveness in OVA-challenged BALB/c mice. Supporting these data, the augmentation of Th2 cytokines (IL-4, IL-5, and IL-13), eotaxin, and adhesion molecules in lung tissues and bronchoalveolar lavage fluid after OVA inhalation was markedly attenuated by PLE. Furthermore, PLE reduced OVA-induced activation of NF-κB and p38 MAPK in lung tissues. Therefore, our results suggest the potential of P. linteus as a therapeutic agent for asthma.


Transglutaminase 2 cross-linking activity is linked to invadopodia formation and cartilage breakdown in arthritis.
The microenvironment surrounding inflamed synovium leads to the activation of fibroblast-like synoviocytes (FLSs), which are important contributors to cartilage destruction in rheumatoid arthritic (RA) joints. Transglutaminase 2 (TG2), an enzyme involved in extracellular matrix (ECM) cross-linking and remodeling, is activated by inflammatory signals. This study was undertaken to assess the potential contribution of TG2 to FLS-induced cartilage degradation. Transglutaminase (TGase) activity and collagen degradation were assessed with the immunohistochemistry of control, collagen-induced arthritic (CIA) or TG2 knockdown (shRNA)-treated joint tissues. TGase activity in control (C-FLS) and arthritic (A-FLS) rat FLSs was measured by in situ 5-(biotinamido)-pentylamine incorporation. Invadopodia formation and functions were measured in rat FLSs and cells from normal (control; C-FLS) and RA patients (RA-FLS) by in situ ECM degradation. Immunoblotting, enzyme-linked immunosorbent assay (ELISA), and p3TP-Lux reporter assays were used to assess transforming growth factor-β (TGF-β) production and activation. TG2 and TGase activity were associated with cartilage degradation in CIA joints. In contrast, TGase activity and cartilage degradation were reduced in joints by TG2 knockdown. A-FLSs displayed higher TGase activity and TG2 expression in ECM than did C-FLSs. TG2 knockdown or TGase inhibition resulted in reduced invadopodia formation in rat and human arthritic FLSs. In contrast, increased invadopodia formation was noted in response to TGase activity induced by TGF-β, dithiothreitol (DTT), or TG2 overexpression. TG2-induced increases in invadopodia formation were blocked by TGF-β neutralization or inhibition of TGF-βR1. TG2, through its TGase activity, is required for ECM degradation in arthritic FLS and CIA joints. Our findings provide a potential target to prevent cartilage degradation in RA.


Translational Factor eIF4G1 Regulates Glucose Homeostasis and Pancreatic β-Cell Function.
Protein translation is essential for cell physiology, and dysregulation of this process has been linked to aging-related diseases such as type 2 diabetes. Reduced protein level of a requisite scaffolding protein of the initiation complex, eIF4G1, downstream of nutrients and insulin signaling is associated with diabetes in humans and mice. In the current study, we tested the hypothesis that eIF4G1 is critical for β-cell function and glucose homeostasis by genetically ablating eIF4G1 specifically in β-cells in vivo (βeIF4G1 knockout [KO]). Adult male and female βeIF4G1KO mice displayed glucose intolerance but normal insulin sensitivity. β-Cell mass was normal under steady state and under metabolic stress by diet-induced obesity, but we observed increases in proliferation and apoptosis in β-cells of βeIF4G1KO. We uncovered deficits in insulin secretion, partly due to reduced mitochondrial oxygen consumption rate, glucose-stimulated Ca2+ flux, and reduced insulin content associated with loss of eIF4E, the mRNA 5' cap-binding protein of the initiation complex and binding partner of eIF4G1. Genetic reconstitution of eIF4E in single β-cells or intact islets of βeIF4G1KO mice recovers insulin content, implicating an unexplored role for eIF4G1/eIF4E in insulin biosynthesis. Altogether these data demonstrate an essential role for the translational factor eIF4G1 on glucose homeostasis and β-cell function.


p53 mutations change phosphatidylinositol acyl chain composition.
Phosphatidylinositol phosphate (PIP) second messengers relay extracellular growth cues through the phosphorylation status of the inositol sugar, a signal transduction system that is deregulated in cancer. In stark contrast to PIP inositol head-group phosphorylation, changes in phosphatidylinositol (PI) lipid acyl chains in cancer have remained ill-defined. Here, we apply a mass-spectrometry-based method capable of unbiased high-throughput identification and quantification of cellular PI acyl chain composition. Using this approach, we find that PI lipid chains represent a cell-specific fingerprint and are unperturbed by serum-mediated signaling in contrast to the inositol head group. We find that mutation of Trp53 results in PIs containing reduced-length fatty acid moieties. Our results suggest that the anchoring tails of lipid second messengers form an additional layer of PIP signaling in cancer that operates independently of PTEN/PI3-kinase activity but is instead linked to p53.


Thrombus Neutrophil Extracellular Traps Content Impair tPA-Induced Thrombolysis in Acute Ischemic Stroke.
Neutrophil Extracellular Traps (NETs) are DNA extracellular networks decorated with histones and granular proteins produced by activated neutrophils. NETs have been identified as major triggers and structural factors of thrombosis. A recent study designated extracellular DNA threads from NETs as a potential therapeutic target for improving tissue-type plasminogen activator (tPA)-induced thrombolysis in acute coronary syndrome. The aim of this study was to assess the presence of NETs in thrombi retrieved during endovascular therapy in patients with acute ischemic stroke (AIS) and their impact on tPA-induced thrombolysis. We analyzed thrombi from 108 AIS patients treated with endovascular therapy. Thrombi were characterized by hematoxylin/eosin staining, immunostaining, and ex vivo enzymatic assay. Additionally, we assessed ex vivo the impact of deoxyribonuclease 1 (DNAse 1) on thrombolysis of AIS thrombi. Histological analysis revealed that NETs contributed to the composition of all AIS thrombi especially in their outer layers. Quantitative measurement of thrombus NETs content was not associated with clinical outcome or AIS pathogenesis but correlated significantly with endovascular therapy procedure length and device number of passes. Ex vivo, recombinant DNAse 1 accelerated tPA-induced thrombolysis, whereas DNAse 1 alone was ineffective. This study suggests that thrombus NETs content may be responsible for reperfusion resistance, including mechanical or pharmacological approaches with intravenous tPA, irrespectively of their etiology. The efficacy of a strategy involving an administration of DNAse 1 in addition to tPA should be explored in the setting of AIS. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02907736.


Diagnosis and long-term management of post-traumatic seizures in a white-crowned pionus (Pionus senilis).
A 13-year-old female white-crowned pionus (Pionus senilis) was examined because of seizures 22 months after it was treated for a traumatic brain injury (TBI) characterized by vision loss, hemiparesis, nystagmus, circling, and head tilt. Bloodwork performed during the initial seizure workup revealed hypercalcemia and hypercholesterolemia, which were attributed to vitellogenesis given the bird's previous egg-laying history and recent onset of reproductive behavior. Magnetic resonance imaging of the brain revealed diffuse right pallium atrophy with multifocal hydrocephalus ex vacuo, which were believed to be the result of the previous TBI. Findings were most consistent with post-traumatic seizures (PTS). Levetiracetam (100 mg/kg [45 mg/lb], PO, q 12 h) was initiated for PTS management. A 4.7-mg deslorelin implant was injected SC to suppress reproductive behavior. The bird was reexamined for presumed status epilepticus 5 times over 22 months. Seizure episodes coincided with onset of reproductive behavior. The levetiracetam dosage was increased (150 mg/kg [68 mg/lb], PO, q 8 h), and zonisamide (20 mg/kg [9.1 mg/lb], PO, q 12 h) was added to the treatment regimen. Additional deslorelin implants were administered every 2 to 6 months to suppress reproductive behavior. The owner was trained to administer midazolam intranasally or IM as needed at home. The treatment regimen helped control but did not eliminate seizure activity. The bird was euthanized 22 months after PTS diagnosis for reasons unrelated to the TBI or PTS. Long-term management of PTS in a pionus was achieved with levetiracetam and zonisamide administration.


Single-fraction radiosurgery of benign cavernous sinus meningiomas.
Stereotactic radiosurgery (SRS) is an important treatment option for patients with cavernous sinus meningiomas (CSM). To analyze factors associated with local tumor control and complications after single-fraction SRS, the authors reviewed cases involving patients treated with Gamma Knife SRS between 1990 and 2008. Excluded were patients with WHO Grade II or III tumors, radiation-induced tumors, multiple meningiomas, neurofibromatosis Type 2, and prior or concurrent radiotherapy. Five patients were lost to follow-up and 3 patients refused research authorization. The remaining 115 patients (29 men, 86 women) had either histologically confirmed WHO Grade I (n = 46, 40%) or presumed (n = 69, 60%) CSM. The median treatment volume was 9.3 cm(3) (range 1.3-42.2 cm(3)). The median margin dose was 16 Gy (range 12-20 Gy). The median follow-up after SRS was 89 months (range 12-251 months). Thirty-nine patients (34%) had 10 or more years of follow-up after SRS. Six patients (5%) had tumor progression (in field, n = 3; marginal, n = 3) at a median of 74 months (range 42-145 months) after SRS. The local tumor control rate was 99% at 5 years and 93% at 10 years after SRS. No analyzed factor was associated with local control after SRS. Fourteen patients (12%) had permanent complications at a median onset of 23 months (range 2-146 months) including trigeminal dysfunction (n = 9), diplopia (n = 2), ischemic stroke (n = 2), and hypopituitarism (n = 1). The 2-year, 5-year, and 10-year rates of complications were 7%, 10%, and 15%, respectively. Multivariate analysis found larger treatment volume (HR 1.1, 95% CI 1.02-1.2, p = 0.01) to be associated with complications after SRS. The complication rate for patients with a treatment volume of 9.3 cm(3) or less was 3% (2 of 58 cases) compared with 21% (12 of 57 cases) for patients with a treatment volume greater than 9.4 cm(3). Single-fraction SRS at the radiation doses used in this series provided durable tumor control for patients with benign CSM. Larger tumor volume remains the primary factor associated with complications after single-fraction SRS of benign CSM despite advancements in SRS technique.


One-Dimensional van der Waals Heterojunction Diode.
The synthesis of one-dimensional van der Waals heterostructures was realized recently, which offers alternative possibilities for prospective applications in electronics and optoelectronics. The even reduced dimension will enable different properties and further miniaturization beyond the capabilities of their two-dimensional counterparts. The natural doping results in p-type electrical characteristics for semiconducting single-walled carbon nanotubes and n-type for molybdenum disulfide with conventional noble metal contacts. Therefore, we demonstrate here a one-dimensional heterostructure nanotube, 11 nm wide, with the coaxial assembly of a semiconducting single-walled carbon nanotube, insulating boron nitride nanotube, and semiconducting molybdenum disulfide nanotube, which induces a radial semiconductor-insulator-semiconductor heterojunction. When opposite potential polarity was applied on a semiconducting single-walled carbon nanotube and molybdenum disulfide nanotube, respectively, the rectifying effect was materialized.


Elucidation of the phenotypic spectrum and genetic landscape in primary and secondary microcephaly.
Microcephaly is a sign of many genetic conditions but has been rarely systematically evaluated. We therefore comprehensively studied the clinical and genetic landscape of an unselected cohort of patients with microcephaly. We performed clinical assessment, high-resolution chromosomal microarray analysis, exome sequencing, and functional studies in 62 patients (58% with primary microcephaly [PM], 27% with secondary microcephaly [SM], and 15% of unknown onset). We found severity of developmental delay/intellectual disability correlating with severity of microcephaly in PM, but not SM. We detected causative variants in 48.4% of patients and found divergent inheritance and variant pattern for PM (mainly recessive and likely gene-disrupting [LGD]) versus SM (all dominant de novo and evenly LGD or missense). While centrosome-related pathways were solely identified in PM, transcriptional regulation was the most frequently affected pathway in both SM and PM. Unexpectedly, we found causative variants in different mitochondria-related genes accounting for ~5% of patients, which emphasizes their role even in syndromic PM. Additionally, we delineated novel candidate genes involved in centrosome-related pathway (SPAG5, TEDC1), Wnt signaling (VPS26A, ZNRF3), and RNA trafficking (DDX1). Our findings enable improved evaluation and genetic counseling of PM and SM patients and further elucidate microcephaly pathways.


Effect of alpha-KG in lumen on PAH transport by isolated perfused rabbit renal proximal tubules.
To determine whether dicarboxylate taken up at the luminal membrane could function in the p-aminohippurate (PAH) countertransport at the basolateral membrane, we examined the effect of adding alpha-ketoglutarate (alpha-KG) or glutarate (a nonmetabolized dicarboxylate that is countertransported for PAH at the basolateral membrane) to the luminal perfusate on net secretion of radiolabeled PAH in isolated perfused S2 segments of rabbit proximal tubules. Addition of 100 microM alpha-KG or glutarate to the luminal perfusate in tubules perfused and bathed with HEPES-buffered medium (in the absence of bicarbonate, glycine, lactate, malate, and citrate) produced a reversible twofold stimulation of net PAH transepithelial secretion. Addition of 4 mM LiCl (an inhibitor of Na-dicarboxylate transport that does not directly affect PAH transport) to the luminal perfusate along with alpha-KG eliminated stimulation of net PAH secretion. Addition of 100 microM or 1 mM alpha-KG or glutarate to the luminal perfusate in tubules perfused and bathed with bicarbonate-buffered medium containing glycine, lactate, malate, and citrate had no effect on net PAH transport from bath to lumen. These data indicate that alpha-KG (or glutarate) that enters the tubule cells via the luminal Na-dicarboxylate cotransporter can stimulate net PAH secretion, apparently via countertransport at the basolateral membrane, but only when tubules are not in an optimal metabolic state to produce intracellular alpha-KG.


Levels of caspase-1 in cerebrospinal fluid of patients with traumatic brain injury: correlation with intracranial pressure and outcome.
The objectives of this study were to evaluate levels of inflammasome-signaling proteins in serum and CSF of patients with traumatic brain injury (TBI), and to correlate these protein levels with intracranial pressure (ICP) and clinical outcomes at 6 months after injury. This is a prospective and observational study in patients with moderate and severe TBI who required an external ventricular drain as part of their treatment. Serum and CSF samples were collected 3 times a day for the first 5 days after TBI. The authors have determined the protein concentration of caspase-1 in the CSF and serum of patients with TBI by using commercially available enzyme-linked immunosorbent assays. The ICP value was recorded hourly. The 6-month outcome was assessed using the Glasgow Outcome Scale-Extended. A total of 21 patients were included in this study, and a total of 234 paired serum-CSF samples were analyzed. The area under the curve (AUC) value of caspase-1 in CSF during the 5-day period was 2452.9 pg/mL·hr in the group of patients with high ICP vs 617.6 pg/mL·hr in the patients with low ICP. The differences were mainly on day 2 (19.7 pg/mL vs 1.8 pg/mL; p = 0.06) and day 3 (13.9 pg/mL vs 1 pg/mL; p = 0.05). The AUC value of caspase in CSF during the 5-day period was 1918.9 pg/mL·hr in the group of patients with poor outcome versus 924.5 pg/mL·hr in the patients with good outcome. The protein levels of caspase-1 in CSF were higher in patients with unfavorable outcomes during the first 96 hours after TBI. In this cohort of patients with TBI who were admitted to the neurosurgical ICU, the inflammasome protein caspase-1 is increased in the CSF of patients with high ICP, especially on days 2 and 3 after TBI. Also the protein levels of caspase-1 in CSF were higher in patients with poor outcome during the first 96 hours after TBI. Moreover, not only the absolute value of caspase-1 in CSF but also its trend is associated with poor outcomes.


Novel lanthanide-labeled metal oxide nanoparticles improve the measurement of in vivo clearance and translocation.
The deposition, clearance and translocation of europium-doped gadolinium oxide nanoparticles in a mouse lung were investigated experimentally. Nanoparticles were synthesized by spray flame pyrolysis. The particle size, crystallinity and surface properties were characterized. Following instillation, the concentrations of particles in organs were determined with inductively coupled plasma mass spectrometry. The protein corona coating the nanoparticles was found to be similar to the coating on more environmentally relevant nanoparticles such as iron oxide. Measurements of the solubility of the nanoparticles in surrogates of biological fluids indicated very little propensity for dissolution, and the elemental ratio of particle constituents did not change, adding further support to the contention that intact nanoparticles were measured. The particles were intratracheally instilled into the mouse lung. After 24 hours, the target organs were harvested, acid digested and the nanoparticle mass in each organ was measured by inductively coupled plasma mass spectrometry (ICP-MS). The nanoparticles were detected in all the studied organs at low ppb levels; 59% of the particles remained in the lung. A significant amount of particles was also detected in the feces, suggesting fast clearance mechanisms. The nanoparticle system used in this work is highly suitable for quantitatively determining deposition, transport and clearance of nanoparticles from the lung, providing a quantified measure of delivered dose.


Acute changes in handgrip strength, endurance, and blood lactate with sustained sport rock climbing.
Modern rock climbers stress the importance of hand-to-rock contact strength as a factor for success in competitive sport climbing events, however, the degree of handgrip fatigue that occurs during difficult climbing and the time course of recovery from fatigue have not been previously described. The purpose of this study was to characterize the nature of handgrip fatigue that results from difficult continuous climbing until a fall occurs. Eleven expert-level rock climbers (age = 28.7 +/- 4.5 years) volunteered to climb continuous laps over a pre-set competition-type route on an indoor modular climbing wall until a fall occurred. The route difficulty (YDS rating of 5.12 a) was near the limit of each subject's "on-sight" lead climbing ability and placed an emphasis on physically difficult movements. "On-sight" refers to a climbing style where the climber ascends the route on the first try without falls and without prior viewing or information about the route. Practice was allowed to enable each subject to master the individual technical movements of the route. Fingertip blood samples were obtained 10 min pre-climb, at post-climb, and at 5-, 10-, and 20-min recovery and analyzed for lactate. Maximum handgrip force in Newtons was determined via dynamometry for each hand and averaged for pre-climb, post-climb, and 5-, 10-, and 20-min recovery periods. Right handgrip endurance, defined as the time that the dominant hand handgrip force could be sustained above 70 percent of handgrip strength, was determined pre-climb, post-climb, and at 20-min recovery. Mean climbing time during testing was 12.9 +/- 8.5 min for 2.8 +/- 2.2 laps over the route. Data among measurement times were analyzed using a repeated measures ANOVA with Newman-Keuls post hoc tests. Handgrip strength decreased by 22 percent and handgrip endurance decreased by 57 percent from pre-climb to post-climb and both remained depressed after 20 minutes of resting recovery. The pre-climb blood lactate of 1.4 +/- 0.8 mmol.l-1 significantly increased to 6.1 +/- 1.4 mmol.l-1 at post-climb and remained elevated (2.3 +/- 0.8 mmol.l-1) at 20-min recovery. Percent decreases in handgrip strength were significantly correlated with climbing time (R = 0.70), number of laps completed (R = 0.70), and blood lactate (R = 0.76). Percent decreases in handgrip endurance were significantly correlated with climbing time (R = 0.70) and number of laps completed (R = 0.80), but not with blood lactate (R = 0.56). It was concluded that handgrip strength and handgrip endurance decrease with continuous difficult rock climbing and remain depressed after 20 minutes of resting recovery. It also appears that handgrip strength recovers at a faster rate than handgrip endurance.


Epithelial Membrane Protein 2 (EMP2) Promotes VEGF-Induced Pathological Neovascularization in Murine Oxygen-Induced Retinopathy.
Retinopathy of prematurity (ROP) is a leading cause of childhood blindness. ROP occurs as a consequence of postnatal hyperoxia exposure in premature infants, resulting in vasoproliferation in the retina. The tetraspan protein epithelial membrane protein-2 (EMP2) is highly expressed in the retinal pigment epithelium (RPE) in adults, and it controls vascular endothelial growth factor (VEGF) production in the ARPE-19 cell line. We, therefore, hypothesized that Emp2 knockout (Emp2 KO) protects against neovascularization in murine oxygen-induced retinopathy (OIR). Eyes were obtained from wildtype (WT) and Emp2 KO mouse pups at P7, P12, P17, and P21 after normoxia or hyperoxia (P7-P12) exposure. Following hyperoxia exposure, RNA sequencing was performed using the retina/choroid layers obtained from WT and Emp2 KO at P17. Retinal sections from P7, P12, P17, and P21 were evaluated for Emp2, hypoxia-inducible factor 1α (Hif1α), and VEGF expression. Whole mount images were generated to assess vaso-obliteration at P12 and neovascularization at P17. Emp2 KO OIR mice demonstrated a decrease in pathologic neovascularization at P17 compared with WT OIR mice through evaluation of retinal vascular whole mount images. This protection was accompanied by a decrease in Hif1α at P12 and VEGFA expression at P17 in Emp2 KO animals compared with the WT animals in OIR conditions. Collectively, our results suggest that EMP2 enhances the effects of neovascularization through modulation of angiogenic signaling. The protection of Emp2 KO mice against pathologic neovascularization through attenuation of HIF and VEGF upregulation in OIR suggests that hypoxia-induced upregulation of EMP2 expression in the neuroretina modulates HIF-mediated neuroretinal VEGF expression.


Tissue donations for multiple sclerosis research: current state and suggestions for improvement.
Although major progress in multiple sclerosis research has been made during the last decades, key questions related to the cause and the mechanisms of brain and spinal cord pathology remain unresolved. These cover a broad range of topics, including disease aetiology, antigenic triggers of the immune response inside and/or outside the CNS and mechanisms of inflammation, demyelination neurodegeneration and tissue repair. Most of these questions can be addressed with novel molecular technologies in the injured CNS. Access to brain and spinal cord tissue from multiple sclerosis patients is, therefore, of critical importance. High-quality tissue is provided in part by the existing brain banks. However, material from early and highly active disease stages is limited. An initiative, realized under the patronage of the European Charcot Foundation, gathered together experts from different disciplines to analyse the current state of multiple sclerosis tissues collected post-mortem or as biopsies. Here, we present an account of what material is currently available and where it can be accessed. We also provide recommendations on how tissue donation from patients in early disease stages could be potentially increased and for procedures of tissue sampling and preservation. We also suggest to create a registry of the available tissues that, depending on the source (autopsy versus biopsy), could be made accessible to clinicians and researchers.


Extracellular ATP stimulates adenylyl cyclase and phospholipase C through distinct purinoceptors in NG108-15 cells.
In neuroblastoma x glioma hybrid NG108-15 cells, ATP induced a concentration-dependent increase in the intracellular Ca2+ concentration ([Ca2+]i), accompanied by inositol phosphate formation. Under the same conditions, we found a marked increase in cAMP levels produced by ATP at concentrations similar to those required to increase [Ca2+]i. The Ca2+ ionophore A23187 or bradykinin, which evoked inositol phosphate formation and increases in [Ca2+]i, did not increase, and instead slightly decreased, cAMP content, indicating that ATP-induced cAMP accumulation was not due to activation of Ca(2+)-sensitive adenylyl cyclase. The effect of ATP on cAMP production was not dependent on generation of adenosine caused by ATP hydrolysis. Among several P2 purinoceptor agonists, adenosine-5'-O-(3-thio)triphosphate, 5'-adenylylimidodiphosphate, and adenosine-5'-O-(2-thio)diphosphate evoked both cAMP accumulation and Ca2+ mobilization. In contrast, beta,gamma-methylene-ATP selectively elicited cAMP accumulation, whereas 2-methylthio-ATP and UTP induced only Ca2+ mobilization, without affecting cAMP levels. The potent P2x purinoceptor agonist alpha,beta-methylene-ATP did not induce cAMP accumulation or Ca2+ mobilization. The cAMP accumulation induced by ATP was not affected by the P2 receptor antagonist suramin but was inhibited by P1 receptor antagonists such as 8-(p-sulfophenyl)theophylline, 3-isobutyl-1-methylxanthine, and xanthine amine congener. However, the ATP-induced increase in [Ca2+]i was not affected by suramin or xanthine amine congener. Taken together, these results indicate that ATP activates two distinct purinoceptors that are coupled to different signal transduction systems, one being adenylyl cyclase and the other phospholipase C, in NG108-15 cells. Furthermore, pharmacological profiles of the adenylyl cyclase-coupled receptor were quite different from those of any known purinoceptor subtypes, especially in the unusual sensitivity of the receptor to P1 and P2 receptor agonists and antagonists. It is therefore suggested that ATP-induced cAMP accumulation may be mediated by a novel subtype of purinoceptor in NG108-15 cells.


Quantifying Gauche Defects and Phase Evolution in Self-Assembled Monolayers through Sessile Drops.
Self-assembled monolayers (SAMs) are widely used in surface modifications, specifically in tuning the surface chemistry of materials. The structure and properties of SAMs have been extensively studied often with sophisticated tools, even for the simplest n-alkanethiolate SAMs. In SAMs, especially in linear n-alkanethiolates, the properties are dependent on the chain length, which is best manifested in the so-called odd-even effect, a simple yet not fully understood phenomenon. One main challenge is fully delineating the origin of length-dependent properties, which can be due to the structure (ideal SAMs), defect evolution, or substrate-molecule effects. This study demonstrates that utilizing the wetting behavior of polar (water) and nonpolar (hexadecane (HD)) solvents on n-alkanethiolate SAMs formed on ultraflat gold and silver surfaces, the evolution of chain-length-dependent gauche defects can be revealed and parameterized through a newly defined dimensionless number (χ). The observation of the odd-even effect in hydrophobicity, however, depends on the thiol chain length, and it was only observed on longer-chain (>C8) molecules. The trend in this odd-even effect demonstrates that there are three main transitions in the nature of wetting, hence structure, across n-alkanethiols. From wetting with HD, the role of dispersive components in wetting reveal that the SAMs are dynamic, which we attribute to rotations associated with previously reported evolution in gauche defects and changes in packing density. Therefore, from re-expression of the Young-Dupre equation, we define a new dimensionless number associated with molecular conformations, whose periodicity mirrors the energetics of Goodman's conformations of n-alkanes in unbound states and associated four- or two-twist turns. Therefore, we infer that the evolution in surface energy is largely due to molecular conformations and associated relaxations of the bound thiolates.


Acoustic changes of the voice as signs of vocal fatigue in radio broadcasters: preliminary findings.
Vocal fatigue is one of the most common voice symptoms. It usually refers to the sensation of vocal tiredness after a long period of speaking or singing. The purpose of this study was to compare the acoustic characteristics of the voice before and after a long period of voice use in a group of radio broadcasters. Eight radio broadcasters with normal voices were assessed. We used cepstrum, energy ratio, noise to harmonic ratio and soft phonation index as acoustic variables to assess the possible pre-post vocal loading changes objectively. There were no statistically significant pre-post differences in any of the acoustic parameters. Although cepstrum at high pitch did not show a significant difference, it obtained the greatest difference among the acoustic variables. The acoustic measurements used in the present study might not be sensitive enough or appropriate for detecting vocal changes after a long period of voice use, whether in reading (as reported in previous research) or speaking tasks. Moreover, a longer period of vocal loading would eventually reveal more evident and consistent acoustic voice changes.


High-throughput informative single nucleotide polymorphism-based typing of Neisseria gonorrhoeae using the Sequenom MassARRAY iPLEX platform.
Neisseria gonorrhoeae antimicrobial resistance (AMR) is a global problem heightened by emerging resistance to ceftriaxone. Appropriate molecular typing methods are important for understanding the emergence and spread of N. gonorrhoeae AMR. We report on the development, validation and testing of a Sequenom MassARRAY iPLEX method for multilocus sequence typing (MLST)-style genotyping of N. gonorrhoeae isolates. An iPLEX MassARRAY method (iPLEX14SNP) was developed targeting 14 informative gonococcal single nucleotide polymorphisms (SNPs) previously shown to predict MLST types. The method was initially validated using 24 N. gonorrhoeae control isolates and was then applied to 397 test isolates collected throughout Queensland, Australia in the first half of 2012. The iPLEX14SNP method provided 100% accuracy for the control isolates, correctly identifying all 14 SNPs for all 24 isolates (336/336). For the 397 test isolates, the iPLEX14SNP assigned results for 5461 of the possible 5558 SNPs (SNP call rate 98.25%), with complete 14 SNP profiles obtained for 364 isolates. Based on the complete SNP profile data, there were 49 different sequence types identified in Queensland, with 11 of the 49 SNP profiles accounting for the majority (n = 280; 77%) of isolates. AMR was dominated by several geographically clustered sequence types. Using the iPLEX14SNP method, up to 384 isolates could be tested within 1 working day for less than Aus$10 per isolate. The iPLEX14SNP offers an accurate and high-throughput method for the MLST-style genotyping of N. gonorrhoeae and may prove particularly useful for large-scale studies investigating the emergence and spread of gonococcal AMR.


Risk of diabetes in the new diagnostic category of impaired fasting glucose: a prospective analysis.
To prospectively evaluate progression to diabetes in individuals with impaired glucose regulation as defined according to fasting glucose alone or an oral glucose tolerance test (OGTT) (i.e., both fasting and postload glucose) to compare the ability of these two screening methods to identify people at high risk of developing diabetes. A working population of 1,245 nondiabetic telephone company employees aged 40-59 years was studied by OGTT in 1980. Participants were classified according to baseline fasting glucose only (as encouraged by the American Diabetes Association [ADA]) or OGTT (as recommended by the 1998 World Health Organization [WHO] consultation). Progression to diabetes was evaluated 11.5 years later according to the 1997 ADA criteria of a fasting plasma glucose level > or =7.0 mmol/l. With the use of the OGTT, baseline prevalence of impaired glucose regulation was substantially higher than that with fasting glucose alone (7.2 vs. 3.2%); the two groups only overlap for 40.9% of the cases because a fairly large number of people with postload hyperglycemia (59.1%) have normal fasting glucose. Progression to diabetes in participants with normal fasting glucose and postload hyperglycemia is significantly more frequent than that of people with normoglycemia (32.5 vs. 7.2%; P < 0.001) and not significantly different from that of people with both fasting and postload hyperglycemia (i.e., 44.0%). However, the former are not identified as being at unusually high risk of diabetes unless an OGTT is performed. When the use of fasting glucose alone or OGTT was validated as a marker of progression to diabetes, sensitivity was substantially higher for the OGTT (33.3 vs. 9.0%) without major differences in specificity (92.6 vs. 97.0%). These data (the only data so far available in Caucasians) support the viewpoint that for the identification of people at high risk of diabetes, the use of the OGTT should be maintained.


The use of C0t-1 probe DNA for the detection of low levels of DNA fragmentation.
In many apoptotic systems the final demise of the DNA results in the generation of multinucleosomal-sized DNA fragments, which appear as a DNA ladder after agarose electrophoresis. Extensive DNA fragmentation can be detected by ethidium bromide staining. Visualization of low levels of DNA fragmentation, however, requires both a more sensitive detection system, as well as a method of DNA extraction, that limits the extent of high molecular weight DNA shearing. We have found that the use of C0t-1 repetitive DNA as a probe for Southern analysis of DNA ladders is a sensitive method to detect low levels of DNA fragmentation. We have applied this methodology in the detection of DNA fragmentation in the normal developing C57BL/6 mouse retina at stages in which there is known DNA fragmentation, as well as in human Y-79 retinoblastoma cells grown in culture. We have found that in many instances in which there is no detectable DNA ladder with ethidium bromide staining a very definitive DNA ladder can be visualized via Southern blot analysis with a C0t-1 DNA probe.


Psychiatric comorbidity among first-time and repeat DUI offenders.
Driving under the influence of alcohol or other substances is a serious public health concern. Previous research has shown that psychiatric comorbidity is more prevalent for repeat offenders than the general population, and that first-time offenders exhibit elevated rates of psychiatric comorbidity, but few studies have directly compared first-time and repeat DUI offenders. The current study compares psychiatric comorbidity among repeat and first-time DUI offenders. First-time and repeat DUI offenders completed the screener module of the Computerized Assessment and Referral System (CARS), adapted from the Composite International Diagnostic Interview (CIDI: Kessler & Ustun, 2004), to measure potential psychiatric comorbidity. For 16 of 19 psychiatric disorders, repeat DUI offenders were more likely to screen positive during their lifetime compared with first-time DUI offenders. Similarly, repeat DUI offenders were more likely to screen positive during the past year for 11 of 16 assessed psychiatric disorders. Overall, repeat DUI offenders screened positive for an average of 6.3 disorders during their lifetime, compared to first-time offenders who screened positive for an average of 3.7 disorders. Repeat DUI offenders also screened positive for more past-year disorders (M = 3.3) than first-time offenders (M = 1.9). Compared to first-time offenders, repeat DUI offenders evidence more severe and pervasive psychiatric comorbidity. Further research is necessary to determine whether psychiatric comorbidity among first-time offenders directly predicts re-offense. If so, screening for mental health issues among first-offenders could provide valuable information about how best to allocate resources for these offenders.


Dismantling the poverty trap: disability policy for the twenty-first century.
Working-age people with disabilities are much more likely than people without disabilities to live in poverty and not be employed or have shared in the economic prosperity of the late 1990s. Today's disability policies, which remain rooted in paternalism, create a "poverty trap" that recent reforms have not resolved. This discouraging situation will continue unless broad, systemic reforms promoting economic self-sufficiency are implemented, in line with more modern thinking about disability. Indeed, the implementation of such reforms may be the only way to protect people with disabilities from the probable loss of benefits if the federal government cuts funding for entitlement programs. This article suggests some principles to guide reforms and encourage debate and asks whether such comprehensive reforms can be successfully designed and implemented.


Mass media exposure and its impact on family planning in Bangladesh.
This paper analyses mass media exposure and its effect on family planning in Bangladesh using data from the Bangladesh Demographic and Health Survey (BDHS) 1993-94. The findings indicate that radio and television are two important mass media for disseminating family planning information in Bangladesh. However, access to them and exposure to family planning through them are still limited. Slightly more than 40% (42.1%) of respondents reported that they had heard family planning messages via radio, while 17.2% said television, 8.4% said poster and 5.4% said billboard. Respondent's place of residence, education, economic status, geographical region and number of living children appeared to be the most important variable determining mass media exposure to family planning. Multivariate analysis shows that both radio and TV exposure to family planning messages and ownership of a radio and TV have a significant effect on current use of family planning methods. These factors remain significant determinants of contraceptive use, even after controlling socioeconomic and demographic factors. The study reveals that both socioeconomic development policies and family planning programmes with a special emphasis on mass media, especially radio, may have a significant effect on contraceptive use in Bangladesh. The principal policy challenge is to design communications strategies that will reach the less privileged, rural and illiterate people who are by far the majority in Bangladesh.


Palladium-catalyzed coupling reactions of tetrafluoroethylene with arylzinc compounds.
Organofluorine compounds are widely used in all aspects of the chemical industry. Although tetrafluoroethylene (TFE) is an example of an economical bulk organofluorine feedstock, the use of TFE is mostly limited to the production of poly(tetrafluoroethylene) and copolymers with other alkenes. Furthermore, no catalytic transformation of TFE that involves carbon-fluorine bond activation has been reported to date. We herein report the first example of a palladium-catalyzed coupling reaction of TFE with arylzinc reagents in the presence of lithium iodide, giving α,β,β-trifluorostyrene derivatives in excellent yields.


Statistical interferometry based on a fully developed speckle field: an experimental demonstration with noise analysis.
A novel interferometric method named statistical interferometry is proposed and studied. In the method, in contrast to the conventional deterministic interferometry, the complete randomness of the two interfering light fields, i.e., the random interference of the fully developed speckle fields, plays an essential role and is used as a standard of phase in a statistical sense. Preliminary experiments were conducted to verify the validity of the method, followed by a computer simulation. As an experimental result, the accuracy of the measurements of an out-of-plane displacement was confirmed up to lambda/800 by comparison with the heterodyne interferometer. The method has the advantage of simplicity of the optical system required, while at the same time providing high accuracy.


The proteins encoded by the pogo-like Lemi1 element bind the TIRs and subterminal repeated motifs of the Arabidopsis Emigrant MITE: consequences for the transposition mechanism of MITEs.
MITEs (miniature inverted-repeated transposable elements) are a particular class of defective DNA transposons usually present within genomes as high copy number populations of highly homogeneous elements. Although an active MITE, the mPing element, has recently been characterized in rice, the transposition mechanism of MITEs remains unknown. It has been proposed that transposases of related transposons could mobilize MITEs in trans. Moreover, it has also been proposed that the presence of conserved terminal inverted-repeated (TIR) sequences could be the only requirement of MITEs for mobilization, allowing divergent or unrelated elements to be mobilized by a particular transposase. We present here evidence for a recent mobility of the Arabidopsis Emigrant MITE and we report on the capacity of the proteins encoded by the related Lemi1 transposon, a pogo-related element, to specifically bind Emigrant elements. This suggests that Lemi1 could mobilize Emigrant elements and makes the Lemi1/Emigrant couple an ideal system to study the transposition mechanism of MITEs. Our results show that Lemi1 proteins bind Emigrant TIRs but also bind cooperatively to subterminal repeated motifs. The requirement of internal sequences for the formation of proper DNA/protein structure could affect the capacity of divergent MITEs to be mobilized by distantly related transposases.