Development and microstructure of tooth histotypes in the blue shark, Prionace glauca (Carcharhiniformes: Carcharhinidae) and the great white shark, Carcharodon carcharias (Lamniformes: Lamnidae).
Elasmobranchs exhibit two distinct arrangements of mineralized tissues in the teeth that are known as orthodont and osteodont histotypes. Traditionally, it has been said that orthodont teeth maintain a pulp cavity throughout tooth development whereas osteodont teeth are filled with osteodentine and lack a pulp cavity when fully developed. We used light microscopy, scanning electron microscopy, and high-resolution micro-computed tomography to compare the structure and development of elasmobranch teeth representing the two histotypes. As an example of the orthodont histotype, we studied teeth of the blue shark, Prionace glauca (Carcharhiniformes: Carcharhinidae). For the osteodont histotype, we studied teeth of the great white shark, Carcharodon carcharias (Lamniformes: Lamnidae). We document similarities and differences in tooth development and the microstructure of tissues in these two species and review the history of definitions and interpretations of elasmobranch tooth histotypes. We discuss a possible correlation between tooth histotype and tooth replacement and review the history of histotype differentiation in sharks. We find that contrary to a long held misconception, there is no orthodentine in the osteodont teeth of C. carcharias.


Comprehensive Investigation and Analysis of Bulk-Heterojunction Microstructure of High-Performance PCE11:PCBM Solar Cells.
Worldwide research efforts have been devoted to organic photovoltaics in the hope of a large-scale commercial application in the near future. To meet the industrial production requirements, organic photovoltaics that can reach power conversion efficiency (PCE) of over 10% along with promising operational device stability are of utmost interest. In the study, we take PCE11:PCBM as a model system, which can achieve over 11% PCE when processed from nonhalogen solvents, to deeply investigate the morphology-performance-stability correlation. We demonstrate that four batches of PCE11 with varying crystalline properties can achieve similar high performance in combination with PCBM. Careful device optimization is necessary in each case to properly address the requirements for the quite distinct microstructures. The bulk-heterojunction (BHJ) microstructure is comprehensively investigated as a function of the macromolecular weight and crystallinity. It is demonstrated that small differences in morphology significantly affect the kinetics and thermodynamic equilibrium of the BHJ microstructure as well as the photostability and thermal stability of the PCE11:PCBM solar cells.


Infection of Siberian chipmunks (Tamias sibiricus barberi) with Borrelia sp. reveals a low reservoir competence under experimental conditions.
Reservoir competence is a key parameter in understanding the role of host species in the epidemiology of multi-host-especially vector-borne-pathogens. With this aim in view, we studied the reservoir competence of the Siberian chipmunk (Tamias sibiricus barberi) recently introduced into Europe, for the multi-host tick-borne bacteria, Borrelia burgdorferi sl, the agent of Lyme borreliosis. T. sibiricus were experimentally exposed to bites from Ixodes ricinus ticks infected with Borrelia burgdorferi sensu stricto and Borrelia afzelii, with subsequent assessment of bacteremia and antibody responses. Borrelia was detected in chipmunk blood samples, ear biopsies and organ necropsies, and in nymphs used for xenodiagnosis (at one and six months after the initial chipmunk infection) via both serological and molecular methods. In total, eight out of twelve chipmunks showed evidence of infection by Borrelia sp., either by ELISA or PCR. Five chipmunks developed an immune response against the bacteria one month after infection. Borrelia infection in at least one organ was observed in seven animals at 14, 38, 93 or 178 days post-infection. Xenodiagnosis was positive for one chipmunk at 38 days, but no longer at 178 days post-infection. Four chipmunks remained uninfected, despite similar infection pressures to those observed in the field. Taken together, these results suggest that chipmunks can be infected through Borrelia-infected tick bites, and can transmit Borrelia to nymphs, but do not remain persistently infected.


Five tyrosines and two serines in human albumin are labeled by the organophosphorus agent FP-biotin.
Tyrosine 411 of human albumin is an established site for covalent attachment of 10-fluoroethoxyphosphinyl- N-biotinamidopentyldecanamide (FP-biotin), diisopropylfluorophosphate, chlorpyrifos oxon, soman, sarin, and dichlorvos. This work investigated the hypothesis that other residues in albumin could be modified by organophosphorus agents (OP). Human plasma was aggressively treated with FP-biotin; plasma proteins were separated into high and low abundant portions using a proteome partitioning antibody kit, and the proteins were digested with trypsin. The FP-biotinylated tryptic peptides were isolated by binding to monomeric avidin beads. The major sites of covalent attachment identified by mass spectrometry were Y138, Y148, Y401, Y411, Y452, S232, and S287 of human albumin. Prolonged treatment of pure human albumin with chlorpyrifos oxon labeled Y138, Y150, Y161, Y401, Y411, and Y452. To identify the most reactive residue, albumin was treated for 2 h with DFP, FP-biotin, chlorpyrifos oxon, or soman, digested with trypsin or pepsin, and analyzed by mass spectrometry. The most reactive residue was always Tyr 411. Diethoxyphosphate-labeled Tyr 411 was stable for months at pH 7.4. These results will be useful in the development of specific antibodies to detect OP exposure and to engineer albumin for use as an OP scavenger.


Atomically Dispersed Ruthenium Species Inside Metal-Organic Frameworks: Combining the High Activity of Atomic Sites and the Molecular Sieving Effect of MOFs.
Incorporating atomically dispersed metal species into functionalized metal-organic frameworks (MOFs) can integrate their respective merits for catalysis. A cage-controlled encapsulation and reduction strategy is used to fabricate single Ru atoms and triatomic Ru3 clusters anchored on ZIF-8 (Ru1 @ZIF-8, Ru3 @ZIF-8). The highly efficient and selective catalysis for semi-hydrogenation of alkyne is observed. The excellent activity derives from high atom-efficiency of atomically dispersed Ru active sites and hydrogen enrichment by the ZIF-8 shell. Meanwhile, ZIF-8 shell serves as a novel molecular sieve for olefins to achieve absolute regioselectivity of catalyzing terminal alkynes but not internal alkynes. Moreover, the size-dependent performance between Ru3 @ZIF-8 and Ru1 @ZIF-8 is detected in experiment and understood by quantum-chemical calculations, demonstrating a new and promising approach to optimize catalysts by controlling the number of atoms.


Association of Age-related Macular Degeneration With Mortality in Patients With Acquired Immunodeficiency Syndrome; Role of Systemic Inflammation.
To evaluate the relationships among age-related macular degeneration (AMD), mortality, and biomarkers of systemic inflammation in patients with acquired immunodeficiency syndrome (AIDS). Case-control study. In participants with intermediate-stage AMD at enrollment in the Longitudinal Study of the Ocular Complications of AIDS (LSOCA) and 2:1 controls matched for age and sex, cryopreserved baseline plasma specimens were assayed for biomarkers of inflammation, including high-sensitivity C-reactive protein (CRP), interleukin (IL)-6, interferon-γ inducible protein (IP)-10, soluble CD14 (sCD14), soluble CD163 (sCD163), kynurenine/tryptophan (KT) ratio, and intestinal fatty acid binding protein (I-FABP). Main outcome measure was mortality. The study included 189 patients with AMD and 385 controls. In the unadjusted analysis, AMD was associated with mortality (hazard ratio [HR] 1.48; 95% confidence interval [CI] 1.02, 2.15; P = .04). In an adjusted analysis, CRP (HR 1.36; 95% CI 1.08, 1.71; P = .009), IL-6 (HR 1.45; 95% CI 1.11, 1.90; P = .006), and IP-10 (HR 1.41; 95% CI 1.08, 1.84; P = .01) were associated with mortality. In a Cox regression analysis adjusted for human immunodeficiency virus load, blood CD4+ T cell level, CRP, IL-6, and IP-10, the association of AMD with mortality was attenuated (HR 1.08; 95% CI 0.73, 1.59; P = .70), primarily by the addition of the inflammatory biomarkers. These data suggest that the increased mortality observed in patients with AIDS with AMD is, at least in part, a result of systemic inflammation.


Brief report: examining driving behavior in young adults with high functioning autism spectrum disorders: a pilot study using a driving simulation paradigm.
Although it is speculated that impairments associated with autism spectrum disorder (ASD) will adversely affect driving performance, little is known about the actual extent and nature of the presumed deficits. Ten males (18-24 years of age) with a diagnosis of high functioning autism and 10 age matched community controls were recruited for a driving simulation experiment. Driving behavior, skin conductance, heart rate, and eye tracking measurements were collected. The high functioning ASD participants displayed a nominally higher and unvaried heart rate compared to controls. With added cognitive demand, they also showed a gaze pattern suggestive of a diversion of visual attention away from high stimulus areas of the roadway. This pattern deviates from what is presumed to be optimal safe driving behavior and appears worthy of further study.


Phosphate limitation responses in marine green algae are linked to reprogramming of the tRNA epitranscriptome and codon usage bias.
Marine algae are central to global carbon fixation and their productivity is dictated largely by resource availability. Reduced nutrient availability is predicted for vast oceanic regions as an outcome of climate change, however there is much to learn regarding response mechanisms of the tiny picoplankton that thrive in these environments, especially eukaryotic phytoplankton. Here, we investigate responses of the picoeukaryote Micromonas commoda, a green alga found throughout subtropical and tropical oceans. Under shifting phosphate (P) availability scenarios, transcriptomic analyses revealed altered expression of transfer RNA (tRNA) modification enzymes and biased codon usage of transcripts more abundant during P-limiting versus P-replete conditions, consistent with the role of tRNA modifications in regulating codon recognition. To associate the observed shift in expression of the tRNA modification enzyme complement with the tRNAs encoded by M. commoda, we also determined the tRNA repertoire of this alga revealing potential targets of the modification enzymes. Codon usage bias was particularly pronounced in transcripts encoding proteins with direct roles in managing P-limitation and photosystem-associated proteins that have ill-characterized putative functions in "light stress". The observed codon usage bias corresponds to a proposed stress response mechanism in which the interplay between stress-induced changes in tRNA modifications and skewed codon usage in certain essential response genes drives preferential translation of the encoded proteins. Collectively, we expose a potential underlying mechanism for achieving growth under enhanced nutrient limitation, that extends beyond the catalog of up- or down-regulated protein-encoding genes, to the cell biological controls that underpin acclimation to changing environmental conditions.


Milk concentration of the mammalian lignan enterolactone, milk production, milk fatty acid profile, and digestibility in dairy cows fed diets containing whole flaxseed or flaxseed meal.
A total of 24 lactating Holstein cows averaging 620 (SE=29) kg of body weight were allotted at week 17 of lactation to eight groups of three cows blocked for similar days in milk to determine the effects of feeding two sources of the plant lignan precursor secoisolariciresinol diglucoside, whole flaxseed and flaxseed meal, on concentrations of the mammalian lignans (enterodiol and enterolactone) in milk. Feed intake, digestion, milk production and milk composition were also determined to compare the use of whole flaxseed and flaxseed meal for milk production. Cows within each block were assigned to one of the three isonitrogenous and isoenergetic total mixed diets: no flaxseed product; 10% flaxseed meal; or 10% whole flaxseed in the dry matter. The experiment was carried out from week 17 to week 21 of lactation and diets were fed at ad-libitum intake. The mammalian lignan, enterodiol, was not detected in the milk of cows. Cows fed whole flaxseed and flaxseed meal had greater concentrations of enterolactone in milk than those fed the control diet. Feed intake, milk production and milk composition were also similar for all diets, indicating that both flaxseed meal and whole flaxseed are suitable feed ingredients for milk production of cows in mid lactation. The results provide new information on the conversion of plant secoisolariciresinol diglucoside from two flaxseed products into mammalian lignans in dairy cows.


Bi-directional associations between healthy lifestyles and mood disorders in young adults: The Childhood Determinants of Adult Health Study.
Healthy lifestyles prevent cardiovascular disease and are increasingly recognized in relation to mental health but longitudinal studies are limited. We examined bi-directional associations between mood disorders and healthy lifestyles in a cohort followed for 5 years. Participants were aged 26-36 years at baseline (2004-2006) and 31-41 years at follow-up (2009-2011). At follow-up, lifetime mood disorders (depression or dysthymia) were retrospectively diagnosed with the Composite International Diagnostic Interview. A five-item lifestyle score (comprising body mass index, non-smoking, alcohol consumption, leisure time physical activity and healthy diet) was measured at both time points. Linear and log multinomial regression determined if mood disorder before baseline predicted changes in lifestyle (n = 1041). Log binomial regression estimated whether lifestyle at baseline predicted new episodes of mood disorder (n = 1233). Covariates included age, sex, socio-economic position, parental and marital status, social support, major life events, cardiovascular disease history, and self-rated physical and mental health. A history of mood disorder before baseline predicted unfavourable trajectories of lifestyle over follow-up, including somewhat lower risk of improvement [relative risk (RR) 0.76, 95% confidence interval (CI) 0.56-1.03] and greater risk of worsening (RR 1.46, 95% CI 0.99-2.15) of lifestyle independent of confounding factors. Higher lifestyle scores at baseline were associated with a 22% (RR 0.76, 95% CI 0.61-0.95) reduced risk of first episodes of mood disorder, independent of confounding factors. Healthy lifestyles and mood disorders are closely related. Our results suggest that healthy lifestyles may not only reduce cardiovascular disease but also promote mental health.


Transplanted hepatocytes proliferate differently after CCl4 treatment and hepatocyte growth factor infusion.
To understand regulation of transplanted hepatocyte proliferation in the normal liver, we used genetically marked rat or mouse cells. Hosts were subjected to liver injury by carbon tetrachloride (CCl4), to liver regeneration by a two-thirds partial hepatectomy, and to hepatocellular DNA synthesis by infusion of hepatocyte growth factor for comparative analysis. Transplanted hepatocytes were documented to integrate in periportal areas of the liver. In response to CCl4 treatments after cell transplantation, the transplanted hepatocyte mass increased incrementally, with the kinetics and magnitude of DNA synthesis being similar to those of host hepatocytes. In contrast, when cells were transplanted 24 h after CCl4 administration, transplanted hepatocytes appeared to be injured and most cells were rapidly cleared. When hepatocyte growth factor was infused into the portal circulation either subsequent to or before cell transplantation and engraftment, transplanted cell mass did not increase, although DNA synthesis rates increased in cultured primary hepatocytes as well as in intact mouse and rat livers. These data suggested that procedures causing selective ablation of host hepatocytes will be most effective in inducing transplanted cell proliferation in the normal liver. The number of transplanted hepatocytes was not increased in the liver by hepatocyte growth factor administration. Repopulation of the liver with genetically marked hepatocytes can provide effective reporters for studying liver growth control in the intact animal.


Release from incarceration, relapse to opioid use and the potential for buprenorphine maintenance treatment: a qualitative study of the perceptions of former inmates with opioid use disorder.
The United States has the highest rate of incarceration in the world (937 per 100,000 adults). Approximately one-third of heroin users pass through correctional facilities annually. Few receive medication assisted treatment (MAT; either methadone or buprenorphine) for opioid use disorder during incarceration, and nearly three-quarters relapse to heroin use within 3 months of release. This qualitative study investigated barriers to and facilitators of buprenorphine maintenance treatment (BMT) following release from incarceration ("re-entry"). We conducted 21 semistructured interviews of former inmates with opioid use disorder recruited from addiction treatment settings. Interviews were audio-recorded, transcribed, and analyzed using a grounded theory approach. Themes that emerged upon iterative readings of transcripts were discussed by the research team. Participants reported adverse re-entry conditions, including persistent exposure to drug use and stressful life events, which were perceived to contribute to opioid relapse and affected addiction treatment decisions during re-entry. Themes that emerged relating to BMT included: 1) reliance on willpower; 2) fear of dependency on medications; 3) variable exposure to buprenorphine; and 4) acceptability of BMT following relapse. Willpower was perceived to be more important for recovery than medications. Many participants experienced painful withdrawal from methadone during incarceration and were fearful that using MAT would lead to opioid tolerance and painful withdrawal again in the future. Participants reported both positive and negative experiences taking illicit buprenorphine, which affected interest in BMT. Overall, BMT was perceived to be a good treatment option for opioid use disorder that could reduce the risk of re-incarceration. BMT was perceived to be acceptable, but former inmates with opioid use disorder may be reluctant to utilize BMT upon re-entry. Factors limiting utilization of BMT could be mitigated though policy change or interventions. Policies of the criminal justice system (e.g., forced detoxification) may be dissuading former inmates from utilizing effective treatments for opioid use disorder. Interventions that improve education and access to BMT for former inmates with opioid use disorder could facilitate entrance into treatment. Both policy changes and interventions are urgently needed to reduce the negative consequences of opioid relapse following re-entry.


Leukoregulin is a potent inducer of hyaluronan synthesis in cultured human orbital fibroblasts.
Leukoregulin, a 50-kDa glycoprotein lymphokine, can regulate the extracellular matrix in dermal fibroblasts. Here we investigate the effects of leukoregulin on the synthesis of glycosaminoglycans in human orbital fibroblasts. We demonstrate that leukoregulin enhances the incorporation of [3H]glucosamine into glycosaminoglycans. The effect is dose dependent in the concentration range tested (0.1-2 U/ml), is maximal at 1 U/ml, and is time dependent. [3H]glycosaminoglycan accumulation is enhanced 7.67 +/- 1.23-fold (SE, n = 7) in orbital fibroblast strains. Pulse-chase studies indicate that this enhanced accumulation is not a result of a decreased rate of macromolecular degradation. Radiolabeled material induced by leukoregulin is sensitive to Streptomyces hyaluronidase digestion. Dexamethasone (10(-8) M) and cycloheximide (10 micrograms/ml) can block the cytokine's stimulation of hyaluronan synthesis. [35S]sulfate incorporation into glycosaminoglycan is unaffected by leukoregulin. In dermal fibroblasts, leukoregulin increased hyaluronan synthesis 3.66 +/- 0.37-fold (n = 5 strains, P < 0.02 compared with orbit). The increase in hyaluronan synthesis in orbital fibroblasts is substantially greater than that observed previously with other cytokines, making leukoregulin a candidate molecular trigger in Graves' ophthalmopathy.


Diffuse opacities in 12-year-old Hong Kong children--four cross-sectional surveys.
To compare the prevalence and severity of diffuse opacities among subjects whose maxillary incisors developed during periods with different concentrations of fluoride in the Hong Kong public water supply. Standardized intra-oral photographs of random samples of 12-year-old children were collected in 1983, 1991, 2001 and 2010 (n = 2658) in Hong Kong and were assessed for diffuse opacities by a calibrated and blinded examiner. The fluoride concentrations in the public water supply at the times when the enamel on their maxillary incisors developed were 1.0, 0.7, 0.5 and 0.5 ppm, respectively. The mouth prevalence figures for diffuse opacities of these children (based on the maxillary incisors) were 89.3%, 48.5%, 32.4% and 42.1 in the years 1983, 1991, 2001 and 2010, respectively. Variation in the mouth and tooth prevalences of diffuse opacities was apparent among the four different year groups (P < 0.0001). Marked differences in severity of diffuse opacities, in terms of different subtypes and maximum extent of tooth affected, were also observed in association with the year of study (P < 0.001). The prevalence and severity of diffuse opacities among maxillary incisor teeth of Hong Kong children decreased from 1983 and then increased in 2010; however, this change did not fully correspond to the concentration of fluoride in the drinking water during the time of enamel development.


Depression and stress reactivity in metastatic breast cancer.
Cancer-related distress due to the psychological and physical challenges of metastatic breast cancer (MBC) may result in symptoms of depression, which negatively affects quality and may influence quantity of life. This study investigated how depression affects MBC stress reactivity, including autonomic (ANS) and hypothalamic-pituitary-adrenal (HPA) axis function. Forty-five nondepressed and 45 depressed patients with MBC underwent a modified Trier Social Stress Test (TSST) while affect, cardiovascular, respiratory, and cortisol responses were measured. At study entry, depressed compared with nondepressed patients had significantly lower log cortisol waking rise levels (p = .005) but no other HPA differences. Positive affect (p = .025) and high-frequency heart-rate variability (lnHF) (p = .002) were significantly lower at TSST baseline in depressed patients. In response to the TSST, depressed patients reported significantly lower positive (p = .050) and greater negative affect (p = .037) and had significantly reduced lnHF (p = .031). In secondary analyses, at TSST baseline both low-frequency (lnLF) (p = .002) and very-low-frequency (lnVLF) (p = .0001) heart rate variability were significantly lower in the depressed group. In secondary analyses during the TSST, those who were depressed had significantly lower lnVLF (p = .008) and did not increase aortic impedance reactivity as much as did the nondepressed during the stressor (p = .005). Depression in patients with MBC was associated with alterations in autonomic regulation, particularly reductions in respiratory sinus arrhythmia, a measure of cardiac vagal control, at baseline and during the TSST. In addition, depression was associated with blunted HPA response to awakening. Both MBC groups had relative cortisol hyporesponsiveness to acute stress.


Heterogeneous Spin States in Ultrathin Nanosheets Induce Subtle Lattice Distortion To Trigger Efficient Hydrogen Evolution.
The exploration of efficient nonprecious metal eletrocatalysis of the hydrogen evolution reaction (HER) is an extraordinary challenge for future applications in sustainable energy conversion. The family of first-row-transition-metal dichalcogenides has received a small amount of research, including the active site and dynamics, relative to their extraordinary potential. In response, we developed a strategy to achieve synergistically active sites and dynamic regulation in first-row-transition-metal dichalcogenides by the heterogeneous spin states incorporated in this work. Specifically, taking the metallic Mn-doped pyrite CoSe2 as a self-adaptived, subtle atomic arrangement distortion to provide additional active edge sites for HER will occur in the CoSe2 atomic layers with Mn incorporated into the primitive lattice, which is visually verified by HRTEM. Synergistically, the density functional theory simulation results reveal that the Mn incorporation lowers the kinetic energy barrier by promoting H-H bond formation on two adjacently adsorbed H atoms, benefiting H2 gas evolution. As a result, the Mn-doped CoSe2 ultrathin nanosheets possess useful HER properties with a low overpotential of 174 mV, an unexpectedly small Tafel slope of 36 mV/dec, and a larger exchange current density of 68.3 μA cm(-2). Moreover, the original concept of coordinated regulation presented in this work can broaden horizons and provide new dimensions in the design of newly highly efficient catalysts for hydrogen evolution.


Ultrasound-guided platelet-rich plasma injections for the treatment of osteoarthritis of the hip.
To assess the safety and symptomatic changes of IA injections of platelet-rich plasma (PRP) in patients with OA of the hip. Forty patients affected by monolateral severe hip OA were included in the study. Each joint received three IA injections of PRP, which were administered once a week. The primary end point was meaningful pain relief, which was described as a reduction in pain intensity of at least 30% from baseline levels as evaluated by the WOMAC subscale at 6-months post-treatment. The visual analogue scale (VAS) and Harris hip score subscale for pain were used to verify the results. Secondary end points included changes in the level of disability of at least 30% and the percentage of positive responders, i.e. the number of patients that achieved a >30% reduction in pain and disability. Statistically significant reductions in VAS, WOMAC and Harris hip subscores for pain and function were reported at 7 weeks and 6 months (P < 0.05). Twenty-three (57.5%) patients reported a clinically relevant reduction of pain (45%, range 30-71%) as assessed by the WOMAC subscale. Sixteen (40%) of these patients were classified as excellent responders who showed an early pain reduction at 6-7 weeks, which was sustained at 6 months, and a parallel reduction of disability. Side effects were negligible and were limited to a sensation of heaviness in the injection site. This preliminary non-controlled prospective study supported the safety, tolerability and efficacy of PRP injections for pain relief and improved function in a limited number of patients with OA of the hip.


ConvNets with Smooth Adaptive Activation Functions for Regression.
Within Neural Networks (NN), the parameters of Adaptive Activation Functions (AAF) control the shapes of activation functions. These parameters are trained along with other parameters in the NN. AAFs have improved performance of Convolutional Neural Networks (CNN) in multiple classification tasks. In this paper, we propose and apply AAFs on CNNs for regression tasks. We argue that applying AAFs in the regression (second-to-last) layer of a NN can significantly decrease the bias of the regression NN. However, using existing AAFs may lead to overfitting. To address this problem, we propose a Smooth Adaptive Activation Function (SAAF) with a piecewise polynomial form which can approximate any continuous function to arbitrary degree of error, while having a bounded Lipschitz constant for given bounded model parameters. As a result, NNs with SAAF can avoid overfitting by simply regularizing model parameters. We empirically evaluated CNNs with SAAFs and achieved state-of-the-art results on age and pose estimation datasets.


Effects of protriptyline on sleep related disturbances of breathing in restrictive chest wall disease.
The effects of protriptyline on sleep stage distribution and gas exchange have been assessed in eight patients with nocturnal hypoventilation secondary to restrictive chest wall disease. At a dose of 10-20 mg taken when they retired the total sleeping time was unaltered but the proportion of rapid eye movement (REM) sleep fell from 22% to 12% (p less than 0.05). The total time spent at an arterial oxygen saturation of less than 80% decreased (p less than 0.01) and the magnitude of the fall correlated with the reduction in REM sleep (r = 0.67, p less than 0.05). There was also a reduction in the maximum carbon dioxide tension reached during the night (p less than 0.01). The arterial oxygen tension measured diurnally increased (p less than 0.05) from a median of 8.0 kPa (60 mm Hg) to 9.0 kPa (67.5 mm Hg), but the carbon dioxide tension and base excess were unchanged. Anticholinergic side effects were experienced by most patients but did not limit treatment.


Performance-based financing in three humanitarian settings: principles and pragmatism.
Performance based financing (PBF) has been increasingly implemented across low and middle-income countries, including in fragile and humanitarian settings, which present specific features likely to require adaptation and to influence implementation of any health financing programme. However, the literature has been surprisingly thin in the discussion of how PBF has been adapted to different contexts, and in turn how different contexts may influence PBF. With case studies from three humanitarian settings (northern Nigeria, Central African Republic and South Kivu in the Democratic Republic of Congo), we examine why and how PBF has emerged and has been adapted to those unsettled and dynamic contexts, what the opportunities and challenges have been, and what lessons can be drawn. Our comparative case study is based on data collected from a document review, 35 key informant interviews and 16 focus group discussions with stakeholders at national and subnational level in the three settings. Data were analysed in order to describe and compare each setting in terms of underlying fragility features and their implications for the health system, and to look at how PBF has been adopted, implemented and iteratively adapted to respond to acute crisis, deal with other humanitarian actors and involve local communities. Our analysis reveals that the challenging environments required a high degree of PBF adaptation and innovation, at times contravening the so-called 'PBF principles' that have become codified. We develop an analytical framework to highlight the key nodes where adaptations happen, the contextual drivers of adaptation, and the organisational elements that facilitate adaptation and may sustain PBF programmes. Our study points to the importance of pragmatic adaptation in PBF design and implementation to reflect the contextual specificities, and identifies elements (such as, organisational flexibility, local staff and knowledge, and embedded long-term partners) that could facilitate adaptations and innovations. These findings and framework are useful to spark a reflection among PBF donors and implementers on the relevance of incorporating, reinforcing and building on those elements when designing and implementing PBF programmes.


Using the preschool language scale, fourth edition to characterize language in preschoolers with autism spectrum disorders.
The Preschool Language Scale, Fourth Edition (PLS-4; Zimmerman, Steiner, & Pond, 2002) was used to examine syntactic and semantic language skills in preschool children with autism spectrum disorders (ASD) to determine its suitability for use with this population. We expected that PLS-4 performance would be better in more intellectually able children and that receptive skills would be relatively more impaired than expressive abilities, consistent with previous findings in the area of vocabulary. Our sample consisted of 294 newly diagnosed preschool children with ASD. Children were assessed via a battery of developmental measures, including the PLS-4. As expected, PLS-4 scores were higher in more intellectually able children with ASD, and overall, expressive communication was higher than auditory comprehension. However, this overall advantage was not stable across nonverbal developmental levels. Expressive skills were significantly better than receptive skills at the youngest developmental levels, whereas the converse applied in children with more advanced development. The PLS-4 can be used to obtain a general index of early syntax and semantic skill in young children with ASD. Longitudinal data will be necessary to determine how the developmental relationship between receptive and expressive language skills unfolds in children with ASD.


The University of Minnesota Pathway Prediction System: multi-level prediction and visualization.
The University of Minnesota Pathway Prediction System (UM-PPS, http://umbbd.msi.umn.edu/predict/) is a rule-based system that predicts microbial catabolism of organic compounds. Currently, its knowledge base contains 250 biotransformation rules and five types of metabolic logic entities. The original UM-PPS predicted up to two prediction levels at a time. Users had to choose a predicted product to continue the prediction. This approach provided a limited view of prediction results and heavily relied on manual intervention. The new UM-PPS produces a multi-level prediction within an acceptable time frame, and allows users to view prediction alternatives much more easily as a directed acyclic graph.


In vivo comparison of copper blood-pool agents: potential radiopharmaceuticals for use with copper-62.
Two techniques for labeling of albumin with copper-67 (67Cu) and 62Cu were investigated; one using the native Cu(II) binding site of the protein and the other employing a bifunctional chelate, 6-bromoacetamidobenzyl-1,4,8,11-tetraazacyclotetradecane- N,N'N",N"'-tetraacetic acid (Br-benzyl-TETA or BAT), conjugated to the protein. Rat biodistribution experiments with 67Cu demonstrated retention of i.v. 67Cu-benzyl-TETA-albumin in the blood pool identical to co-injected 125I-albumin. By contrast, i.v. administration of either [67Cu]-Cu-acetate or [67Cu]-Cu-acetate pre-mixed with albumin results in relatively rapid clearance of blood-pool radioactivity as the tracer is excreted into the urine. The 62Cu-benzyl-TETA-albumin radiopharmaceutical was obtained in ca. 17% radiochemical yield (end of synthesis, without decay correction) following a procedure that can be completed in 15-18 min. In PET experiments with a baboon, myocardial blood volume images with 62Cu-benzyl-TETA-albumin were identical to those obtained with C15O. Use of the 62Cu-benzyl-TETA-albumin image for blood-pool subtraction of a 62Cu-PTSM myocardial perfusion image is illustrated. Copper-62-benzyl-TETA-HSA should be a useful, generator-produced radiotracer for the detection of the vascular pool at PET facilities without cyclotrons.


Boundary work and the introduction of acute care nurse practitioners in healthcare teams.
This article is a report of a study of boundary work following the introduction of an acute care nurse practitioner role in healthcare teams. Acute care nurse practitioners enacting their roles in healthcare teams have faced a number of challenges including a mix of positive and negative views of the acute care nurse practitioner role from healthcare team members and acute care nurse practitioner roles crossing the boundaries between the medical and nursing professions. Understanding the process by which the boundaries between professions changed following the introduction of an acute care nurse practitioner role was important since this could affect scope of practice and the team's ability to give patient care. The study was conducted in two university-affiliated teaching hospitals in Canada. A descriptive multiple case study design was used. Data were collected from March to May 2009. Participants (N = 59) described boundary work as a process that included: (1) creating space; (2) loss of a valued function; (3) trust; (4) interpersonal dynamics; and (5) time. The development of trust among team members was essential. The co-location of team members working on common projects, and medical and nursing leadership facilitated boundary work. The micro-level processes of boundary work in healthcare teams have important implications for the development of full scope of practice for acute care nurse practitioners, effective inter-professional teamwork and the integration of new roles in healthcare systems. Future research needs to be undertaken in different contexts, and with patients and families.


Sex Differences in Left Ventricular Assist Device-related Emergency Department Encounters in the United States.
There is a paucity of data regarding sex differences in the profiles and outcomes of ambulatory patients on left ventricular assist device (LVAD) support who present to the emergency department (ED). We performed a retrospective analysis of 57,200 LVAD-related ED patient encounters from the 2010 to 2018 Nationwide Emergency Department Sample. International Classification of Diseases Clinical Modification, Ninth Revision and Tenth Revision, codes identified patients aged 18 years or older with LVADs and associated primary and comorbidity diagnoses. Clinical characteristics and outcomes were stratified by sex and compared. Multivariable logistic regression was used to evaluate predictors of hospital admission and death. Female patient encounters comprised 27.2% of ED visits and occurred at younger ages and more frequently with obesity and depression (all P < .01). There were no sex differences in presentation for device complication, stroke, infection, or heart failure (all P > .05); however, female patient encounters were more often respiratory- and genitourinary or gynecological related (both P < .01). After adjustment for age group, diabetes, depression, and hypertension, male patient encounters had a 38% increased odds of hospital admission (95% confidence interval 1.20-1.58), but there was no sex difference in the adjusted odds of death (odds ratio 1.11, 95% confidence interval 0.86-1.45). Patient encounters of females on LVAD support have significantly different comorbidities and outcomes compared with males. Further inquiry into these sex differences is imperative to improve long-term outcomes.


Efficacy of irrigation with rotary instrumentation.
The purpose of this study was to evaluate the efficacy of a handpiece-mounted irrigation device and compare it to irrigation with a syringe and needle in the apical 5 mm of the root canal system. Twenty matched pairs of extracted teeth were used. The only variable within each matched pair was the method of irrigation. A syringe and needle were used in group A and the handpiece-mounted system in group B. Sections 1, 3, and 5 mm from the working length were examined microscopically, and images of the slides were digitized. The percentage of canal space occupied by pulpal and dentinal debris was calculated to be 6% +/- 12.7% in group A, versus 3.8% +/- 7% in group B (p = 0.264). The percentages at each level were as follows: 1 mm from the working length, 14.1% +/- 19% for group A and 5% +/- 7.5% for group B; 3 mm from working length, 1.8% +/- 5.4% for group A and 3.9% +/- 6.9% for group B; and 5 mm from working length, 3.1% +/- 7.7% for group A and 2.6% +/- 7.3% for group B. In group A, there was significantly more debris in the 1-mm section than in the 3- or 5-mm sections. In group B, the differences between levels were not significant. There was no significant difference in the amount of debris remaining in the apical 5 mm of canals when comparing the handpiece-mounted irrigation device to irrigation with a syringe and needle. The average times for instrumentation in group A (needle irrigation) and group B (Quantec-E irrigation system) were 8.7 +/- 2.7 min and 6.5 +/- 1.9 min, respectively. Group B was associated with statistically significant shorter instrumentation time (p < 0.0005). An average of 12.5 +/- 4.9 ml of irrigant was used in group A and 17.3 +/- 4.8 ml in group B. The difference was statistically significant (p < 0.0005).


The native 67-kilodalton minor fimbria of Porphyromonas gingivalis is a novel glycoprotein with DC-SIGN-targeting motifs.
We recently reported that the oral mucosal pathogen Porphyromonas gingivalis, through its 67-kDa Mfa1 (minor) fimbria, targets the C-type lectin receptor DC-SIGN for invasion and persistence within human monocyte-derived dendritic cells (DCs). The DCs respond by inducing an immunosuppressive and Th2-biased CD4(+) T-cell response. We have now purified the native minor fimbria by ion-exchange chromatography and sequenced the fimbria by tandem mass spectrometry (MS/MS), confirming its identity and revealing two putative N-glycosylation motifs as well as numerous putative O-glycosylation sites. We further show that the minor fimbria is glycosylated by ProQ staining and that glycosylation is partially removed by treatment with beta(1-4)-galactosidase, but not by classic N- and O-linked deglycosidases. Further monosaccharide analysis by gas chromatography-mass spectrometry (GC-MS) confirmed that the minor fimbria contains the DC-SIGN-targeting carbohydrates fucose (1.35 nmol/mg), mannose (2.68 nmol/mg), N-acetylglucosamine (2.27 nmol/mg), and N-acetylgalactosamine (0.652 nmol/mg). Analysis by transmission electron microscopy revealed that the minor fimbria forms fibers approximately 200 nm in length that could be involved in targeting or cross-linking DC-SIGN. These findings shed further light on molecular mechanisms of invasion and immunosuppression by this unique mucosal pathogen.


Phonotactic walking paths of field crickets in closed-loop conditions and their simulation using a stochastic model.
Field cricket females localize one of many singing males in the field in closed-loop multi-source conditions. To understand this behaviour, field cricket phonotaxis was investigated in a closed-loop walking phonotaxis paradigm, in response to two simultaneously active speakers playing aphasic calling songs. Female phonotactic paths were oriented towards the louder sound sources, but showed great inter-individual variability. Decisions made in the initial phases were correlated with the overall directions of the paths. Interestingly, the sound pressure levels of stimuli did not greatly influence several features of phonotactic paths such as sinuosity, walking bout lengths and durations. In order to ascertain the extent of our understanding of walking phonotaxis, a stochastic model was used to simulate the behaviour observed in the experiment. The model incorporated data from the experiment and our current understanding of field cricket auditory physiology. This model, based on stochastic turning towards the louder side, successfully recaptured several qualitative and quantitative features of the observed phonotactic paths. The simulation also reproduced the paths observed in a separate outdoor field experiment. Virtual crickets that were unilaterally deafened or had poor ear directionality exhibited walking paths similar to those observed in previous experiments.


The 412 retrotransposon and the development of gonadal mesoderm in Drosophila.
We have shown that the expression of the 412 retrotransposon provides a useful early marker for the development of the gonadal mesoderm in Drosophila embryos. 412 is initially expressed in a set of parasegmentally repeated stripes from parasegments (PS) 2-14 in the mesoderm at the extended germ band stage. During germ band retraction the bulk of 412 expression declines except in dorsolateral clusters of cells in PS10, 11 and 12, where high levels of 412 expression remain. These mesodermal cell clusters are associated with germ cells and subsequently they coalesce, rounding up to form the gonads. The gonadal mesoderm thus appears to originate specifically from three abdominal parasegments, PS10, 11 and 12. We show that the maintenance of high levels of 412 expression in gonadal mesoderm is not induced by contact with germ cells, but rather depends on genetic control by the homeotic genes abdominal-A and Abdominal-B.


Properties of the branched-chain 2-hydroxy acid/2-oxo acid shuttle in mouse spermatozoa.
Operation of the branched-chain 2-hydroxy acid/2-oxo acid shuttle for the transfer of reducing equivalents in mitochondria of mouse spermatozoa was studied in vitro in reconstituted systems. Results show that the branched-chain 2-oxo acids within the mitochondria are offered several metabolic pathways. (a) Decarboxylation: mouse sperm mitochondria possess high branched-chain 2-oxo acid decarboxylase activity. (b) Recycling to the cytosol by using a transport system which can be inhibited by alpha-cyano-3-hydroxycinnamate and pH 6.8. (c) Transamination to the corresponding amino acids: experiments presented indicate that leucine formed from 4-methyl-2-oxopentanoate may pass to the external phase, re-initiating the cycle. These two last possibilities would allow autocatalytic operation of the shuttle. The branched-chain 2-hydroxy acids apparently do not utilize the monocarboxylate carrier to penetrate the mitochondria.


Experiences of apathy in people with Parkinson's disease: a qualitative exploration.
Research has suggested that people with Parkinson's disease (PD) can experience apathy. This study explored the lived experiences of apathy in people with PD. Seven participants with Parkinson's disease who were also described as having apathy were interviewed and the data analysed using interpretative phenomenological analysis. The findings were understood within three overlapping themes: (1) "The apathy creeps into jobs that I used to be able to do and no longer can do": Reduced motivation in response to the consequences of impairment; (2) "I hate at the end of the day if I've achieved nothing": The (un)acceptability of apathy; (3) "They say 'come on you lazy b*gger, get something done'": The social context of apathy. These themes are compared to wider research on apathy, PD and chronic illness. This study offers a view that, for some, apathy may be experienced as a number of behavioural choices influenced by increasing impairment and enacted in a social context. It presents an alternative conceptualisation from one describing apathy as the sole result of an endogenous disease process. As such, a number of therapeutic options are discussed but with the caveat that "apathy" need not always be the focus for intervention. Implications for Rehabilitation Apathy is a term used to denote a decrease in motivation and, although widely used, lacks conceptual clarity. Therefore the personal meaning of the behaviour for the individual within the context of their illness must be considered on assessment. Apathy is a societal as well as personal issue and the therapist also needs to assess the meaning and implications of the behaviour in the individual's social context. Practitioners need to be aware that apathy need not always be a focus for intervention. Discussion around the meaning of the behaviour may be all which is needed. Where individuals do wish to change their behaviours, a number of behavioural and psychological approaches are available. "Third wave" psychological therapies such as compassion- and acceptance-based approaches seem useful although none currently have any evidence base specifically with people with Parkinson's disease.


Impact of geographical region on urinary metabolomic and plasma fatty acid profiles in subjects with the metabolic syndrome across Europe: the LIPGENE study.
The application of metabolomics in multi-centre studies is increasing. The aim of the present study was to assess the effects of geographical location on the metabolic profiles of individuals with the metabolic syndrome. Blood and urine samples were collected from 219 adults from seven European centres participating in the LIPGENE project (Diet, genomics and the metabolic syndrome: an integrated nutrition, agro-food, social and economic analysis). Nutrient intakes, BMI, waist:hip ratio, blood pressure, and plasma glucose, insulin and blood lipid levels were assessed. Plasma fatty acid levels and urine were assessed using a metabolomic technique. The separation of three European geographical groups (NW, northwest; NE, northeast; SW, southwest) was identified using partial least-squares discriminant analysis models for urine (R² X: 0·33, Q²: 0·39) and plasma fatty acid (R² X: 0·32, Q²: 0·60) data. The NW group was characterised by higher levels of urinary hippurate and N-methylnicotinate. The NE group was characterised by higher levels of urinary creatine and citrate and plasma EPA (20 : 5 n-3). The SW group was characterised by higher levels of urinary trimethylamine oxide and lower levels of plasma EPA. The indicators of metabolic health appeared to be consistent across the groups. The SW group had higher intakes of total fat and MUFA compared with both the NW and NE groups (P≤ 0·001). The NE group had higher intakes of fibre and n-3 and n-6 fatty acids compared with both the NW and SW groups (all P< 0·001). It is likely that differences in dietary intakes contributed to the separation of the three groups. Evaluation of geographical factors including diet should be considered in the interpretation of metabolomic data from multi-centre studies.


Retrograde facilitation under midazolam: the role of general and specific interference.
In a double-blind, placebo-controlled experiment that used midazolam, a benzodiazepine that creates temporary amnesia, we compared acquisition and retention of paired associates of different types. Some word pairs were studied before the injection of saline or midazolam, and two lists of word pairs were studied after the injection. Critical comparisons involved retention of pairs that were practiced on all three lists, pairs studied on only one list, and pairs that involved recombining cue and response terms from one list to the next, as a function of drug condition. Previous research with benzodiazepines had found retrograde facilitation for material acquired prior to injection, compared with the control condition. One explanation for this facilitation is that the anterograde amnesia produced by the benzodiazepine frees up the hippocampus to better consolidate previously learned material (Wixted, 2004, 2005). We accounted for a rich data set using a simple computational model that incorporated interference effects (cue overload) at retrieval for both general (experimental context) interference and specific (stimulus term) interference without the need to postulate a role for consolidation. The computational model as an Excel spreadsheet may be downloaded from www.psychonomic.org/archive.


Epidemiological, Clinical, and Psychological Characteristics of Individuals with Self-reported Irritable Bowel Syndrome Based on the Rome IV vs Rome III Criteria.
Few studies have examined the effects of applying the Rome IV criteria for irritable bowel syndrome (IBS) vs the previous standard, the Rome III criteria. We conducted a cross-sectional survey of individuals who self-identify as having IBS to examine this issue. We collected complete demographic, symptom, mood, and psychological health data from 1375 adults who self-identified as having IBS, but were not recruited from a referral population. We applied the Rome III and the Rome IV criteria simultaneously to examine what proportion met each of these diagnostic criteria for IBS. We measured the level of agreement between the Rome III and Rome IV criteria, and assessed for presence of an alternative functional bowel disorder in individuals who no longer met diagnostic criteria for IBS with the more restrictive Rome IV criteria. Finally, we compared characteristics of individuals who met only Rome III criteria with those who met Rome IV criteria. In total, 1080 of 1368 individuals (78.9%) with IBS met the Rome III criteria. In contrast, 811 of 1373 individuals (59.1%) with IBS met the Rome IV criteria. Agreement between the criteria was only moderate (Kappa = 0.50). Among those who no longer had IBS according to the Rome IV criteria, 33 (11.5%) met Rome IV criteria for functional constipation, 118 (41.3%) for functional diarrhea, 68 (23.8%) for functional abdominal bloating or distension, and 67 (23.4%) for an unspecified functional bowel disorder. Individuals with Rome IV-defined IBS had more severe symptoms, and a higher proportion had a mood disorder and evidence of poor psychological health, compared with individuals who only met the Rome III criteria for IBS (P < .001). The characteristics of people who believe they have IBS differ between those who meet criteria as defined by Rome IV vs Rome III, including the spectrum of disease severity. Studies are needed to determine how these changes will affect outcomes of clinical trials.


Falls prediction in elderly people: a 1-year prospective study.
The aim of the present study was to determine whether force plate variables in single- and dual-task situations are able to predict the risk of multiple falls in a community-dwelling elderly population. Two hundred and seventy elderly persons (225 females, 45 males; age, 73+/-7 years) performed balance assessment with and without vision. Seven force plate variables were assessed to predict the risk of multiple falls; maximum displacement in the anteroposterior and medial-lateral directions (Max-AP, Max-ML), mean displacement in the medial-lateral direction (MML), the root mean square amplitude in anteroposterior and medial-lateral directions (RMS-AP, RMS-ML), the average speed of displacement (V), and the area of the 95th percentile ellipse (AoE). Falls were prospectively recorded during the following year. A total of 437 registered falls occurred during monitoring period. The force plate variable RMS-ML in the single-task condition (odds ratio, 21.8) predicted multiple falls together with the following covariables: history of multiple falls (odds ratio, 5.6), use of medications (fall-risk medications or multiple medicine use; odds ratio, 2.3), and gender (odds ratio, 0.34). Multiple fallers had a narrower stance width than non-fallers.


Biologic therapies in clinical development for the treatment of rheumatoid arthritis.
The therapeutic objective in patients with rheumatoid arthritis (RA) is reduction of disease activity with an ultimate goal of disease remission. Limitations of currently available disease-modifying antirheumatic drugs and biologic therapies suggest that there remains an unmet need for agents that advance these goals in a greater proportion of patients. Progress in our understanding of the regulatory molecules and pathways that mediate the immune and inflammatory responses necessary for the initiation and perpetuation of RA has led to the identification of new targets for therapy. It is expected that the therapeutic modulation of these targets, which include proinflammatory cytokines, T and B cells, adhesion molecules, chemokines, and intra- and extracellular signaling pathways, can provide new treatment strategies in patients with RA and other autoimmune disorders. Toward this end, a series of novel agents with diverse mechanisms of action are in development. Although many of these agents are still beyond the clinical horizon, several of them have shown promise in recent trials. This article reviews a few of the many treatment strategies currently being evaluated, which are hoped to lead to greater benefits and better disease management in the clinical setting.


On cell separation with topographically engineered surfaces.
Topographical modifications of the surface influence several cell functions and can be exploited to modulate cellular activities such as adhesion, migration and proliferation. These complex interactions are cell-type specific, therefore engineered substrates featuring patterns of two or more different topographies may be used to obtain the selective separation of different cell lineages. This process has the potential to enhance the performance of biomedical devices promoting, for example, the local coverage with functional tissues while demoting the onset of inflammatory reactions. Here we present a computational tool, based on Monte Carlo simulation, which decouples the contribution of cell proliferation and migration and predicts the cell-separation performance of topographically engineered substrates. Additionally, we propose an optimization procedure to shape the topographically engineered areas of a substrate and obtain maximal cell separation.


Bacterial vaginosis in female facility workers in north-western Tanzania: prevalence and risk factors.
To determine prevalence of, and risk factors for, bacterial vaginosis (BV) among herpes simplex virus (HSV) 2 seropositive Tanzanian women at enrollment into a randomised, placebo-controlled trial of HSV suppressive treatment. 1305 HSV-2 seropositive women aged 16-35 years working in bars, guesthouses and similar facilities were interviewed, examined and tested for HIV, syphilis, Neisseria gonorrhoeae, Chlamydia trachomatis, BV, candidiasis and trichomoniasis. Factors associated with BV were analysed using logistic regression to estimate odds ratios and 95% confidence intervals. BV prevalence was 62.9%; prevalence of Nugent score 9-10 was 16.1%. Independent risk factors for BV were work facility type, fewer dependents, increasing alcohol consumption, sex in the last week (adjusted OR 2.03; 95% CI 1.57 to 2.62), using cloths or cotton wool for menstrual hygiene, HIV (adjusted OR 1.41; 95% CI 1.09 to 1.83) and Trichomonas vaginalis infection. There was no association between BV and the frequency or method of vaginal cleansing. However, BV was less prevalent among women who reported inserting substances to dry the vagina for sex (adjusted OR 0.44; 95% CI 0.25 to 0.75). BV was extremely prevalent among our study population of HSV-2 positive female facility workers in North-western Tanzania. Although recent sex was associated with increased BV prevalence, vaginal drying was associated with lower BV prevalence. Further studies of the effects of specific practices on vaginal flora are warranted.


Live cell plasma membranes do not exhibit a miscibility phase transition over a wide range of temperatures.
Lipid/cholesterol mixtures derived from cell membranes as well as their synthetic reconstitutions exhibit well-defined miscibility phase transitions and critical phenomena near physiological temperatures. This suggests that lipid/cholesterol-mediated phase separation plays a role in the organization of live cell membranes. However, macroscopic lipid-phase separation is not generally observed in cell membranes, and the degree to which properties of isolated lipid mixtures are preserved in the cell membrane remain unknown. A fundamental property of phase transitions is that the variation of tagged particle diffusion with temperature exhibits an abrupt change as the system passes through the transition, even when the two phases are distributed in a nanometer-scale emulsion. We support this using a variety of Monte Carlo and atomistic simulations on model lipid membrane systems. However, temperature-dependent fluorescence correlation spectroscopy of labeled lipids and membrane-anchored proteins in live cell membranes shows a consistently smooth increase in the diffusion coefficient as a function of temperature. We find no evidence of a discrete miscibility phase transition throughout a wide range of temperatures: 14-37 °C. This contrasts the behavior of giant plasma membrane vesicles (GPMVs) blebbed from the same cells, which do exhibit phase transitions and macroscopic phase separation. Fluorescence lifetime analysis of a DiI probe in both cases reveals a significant environmental difference between the live cell and the GPMV. Taken together, these data suggest the live cell membrane may avoid the miscibility phase transition inherent to its lipid constituents by actively regulating physical parameters, such as tension, in the membrane.


Science-based assessment of animal welfare: companion animals.
Human history reveals that the way in which humans treat animals is based on their views of themselves as well as of the living environment around them. These views may vary from an assumption of human superiority to one of equality between humans and animals. Recent trends affecting companion-animal welfare are: modern philosophies on animal issues, the specialised and varied roles that companion animals play in modern societies, new results from animal neuroscience, human-animal interaction studies and the new profession of companion animal ethology. This paper concludes that applied ethology could provide science-based criteria to assess companion-animal welfare. Due to the integral part that companion animals play in human societies, the paper is divided into an animal component that deals with the animal's basic needs and its ability to adapt, and a human component assessing the living environment of animals as provided by humans and responsible companion-animal ownership. The greatest challenge for future research is to find ways to disseminate knowledge of companion animal ethology to companion animal owners.


A new shell disease in the mud crab Scylla serrata from Port Curtis, Queensland (Australia).
In 1994 a previously unreported rust spot shell disease was seen in mud crabs Scylla serrata - Forskal from Port Curtis, central Queensland, Australia. Of 673 crabs surveyed, 21.7% had shell lesions. Of these, 82.9% had rust spot lesions on the carapace. The majority of rust spot-affected crabs (78.8%) were female. Rust spot lesions were predominantly non-perforated (89.4%) and 54.8% were bilaterally symmetrical. There was also a gender difference in the areas of the carapace most commonly affected. The main histological features of the rust spot lesion included: a cavity in the upper endocuticle; indentation of the endocuticle below the cavity; remains of muscle attachment adhesive epithelium within the cavity; fibrous connective tissue between the damaged carapace and the attached muscle; and islands of endocuticle in this fibrous connective tissue. Histopathology of the internal organs failed to find evidence of an infectious or parasitic cause of the rust spot lesions. The cause(s) of the syndrome appear(s) to be non-infectious.


The influence of stimulus size on heterochromatic modulation electroretinograms.
When combined with the electroretinogram (ERG), the heterochromatic flicker photometry procedure allows an objective in vivo assessment of postreceptoral activity. Responses evoked at intermediate (approximately 12 Hz) and high (>30 Hz) temporal frequencies reflect the red-green cone opponent (possibly parvocellular) and the luminance (possibly magnocellular) responses, respectively. Previously, we found that cone-isolating stimuli at intermediate temporal frequencies elicited ERG responses with similar amplitudes and phases for different spatial arrangements of the stimuli, whereas response amplitudes at high temporal frequencies were positively correlated with stimulus size. The purpose of this study was to investigate whether the influence of stimulus size was confined to cone-isolating stimuli or whether it was a general feature of heterochromatic stimulation. Furthermore, we aimed to determine the smallest spatial extent for a significant response in the two postreceptoral mechanisms. Monocular ERGs were recorded to red-green counterphase modulated sinusoidal stimuli (mean luminance of 200 cd/m2) presented at 12 and 36 Hz at different stimulus sizes. At each stimulus condition, a series of ERGs were recorded with the red-contrast fraction (FR) [FR = CR/(CR + CR)] of the stimulus varying between 0.0 and 1.0. Response amplitudes at 36 Hz changed with FR for all subjects, exhibiting a V-shaped amplitude profile with a minimum close to the psychophysics-based isoluminance, where the ERG phase changed by 180°. As stimulus size decreased, the amplitudes to 36 Hz also decreased. In contrast, amplitudes and phases at 12 Hz generally were constant for all values of FR. These amplitudes were invariant to stimulus sizes larger than 10° but decreased with decreasing stimulus size below 10°. Phase also changed in this range. Thus, luminance pathway ERG responses (36 Hz) show direct dependency on stimulus size, whereas chromatic pathway responses (12 Hz) are independent of the stimulus size above 10°.


Interactions of vanadium(iv) with amidoxime ligands: redox reactivity.
The use of amidoxime-functionalized polymer fibers as a sorbent for uranium has attracted recent interest for the extraction of uranium from seawater. Vanadium is one of the main competing ions for uranium sorption as V(v) species, however, vanadium is also present as V(iv) in seawater. In the present study, the interactions of V(iv) with amidoxime and similar ligands were explored. Attempts were made to synthesize V(iv) complexes of glutaroimide-dioxime, a molecular analogue of polymer sorbents. However, V(iv) was found to react irreversibly with glutaroimide-dioxime and other oxime groups, oxidizing to the V(v) oxidation state. We have explored the reactions and propose mechanisms, as well as characterized the redox behavior of the vanadium-glutaroimide-dioxime complex.


The myxoma virus M-T4 gene encodes a novel RDEL-containing protein that is retained within the endoplasmic reticulum and is important for the productive infection of lymphocytes.
To investigate the contribution of the myxoma virus M-T4 gene to viral virulence, both copies of the M-T4 gene were inactivated by disruption and insertion of the Escherichia coli guanosine phosphoribosyltransferase gene. Infection of European rabbits with the recombinant M-T4-deleted virus, vMyxlacT4, resulted in disease attenuation. In contrast, infection of rabbits with vMyxlac elicited the classical features of lethal myxomatosis. A notable decrease in the number of secondary lesions in animals infected with vMyxlacT4 suggested an inability of the virus to disseminate in vivo. Infection of either a rabbit CD4+ T cell line, RL-5, or primary rabbit peripheral blood lymphocytes with vMyxlacT4- resulted in the rapid induction of apoptosis. Sequence analysis of M-T4 revealed both an N-terminal signal sequence and a C-terminal -RDEL sequence, suggesting that M-T4 resides in the endoplasmic reticulum. The M-T4 protein was found to be sensitive to endo H digestion and confocal fluorescence microscopy demonstrated that M-T4 colocalized with calreticulin, indicating that M-T4 is retained within the endoplasmic reticulum. Our results indicate that M-T4 is the first example of an intracellular virulence factor in myxoma virus that functions from within the endoplasmic reticulum and is necessary for the productive infection of lymphocytes.


Genome-wide depletion of replication initiation events in highly transcribed regions.
This report investigates the mechanisms by which mammalian cells coordinate DNA replication with transcription and chromatin assembly. In yeast, DNA replication initiates within nucleosome-free regions, but studies in mammalian cells have not revealed a similar relationship. Here, we have used genome-wide massively parallel sequencing to map replication initiation events, thereby creating a database of all replication initiation sites within nonrepetitive DNA in two human cell lines. Mining this database revealed that genomic regions transcribed at moderate levels were generally associated with high replication initiation frequency. In genomic regions with high rates of transcription, very few replication initiation events were detected. High-resolution mapping of replication initiation sites showed that replication initiation events were absent from transcription start sites but were highly enriched in adjacent, downstream sequences. Methylation of CpG sequences strongly affected the location of replication initiation events, whereas histone modifications had minimal effects. These observations suggest that high levels of transcription interfere with formation of pre-replication protein complexes. Data presented here identify replication initiation sites throughout the genome, providing a foundation for further analyses of DNA-replication dynamics and cell-cycle progression.


Evaluation of paradoxic beneficial effects of smoking in patients receiving thrombolytic therapy for acute myocardial infarction: mechanism of the "smoker's paradox" from the GUSTO-I trial, with angiographic insights. Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries.
Our purpose was to evaluate the relation between smoking and the outcomes of patients receiving thrombolysis for acute myocardial infarction. A paradoxic beneficial effect has been observed in smokers with a myocardial infarction. We analyzed outcomes and baseline characteristics of 11,975 nonsmokers, 11,117 ex-smokers and 17,507 current smokers in a multinational trial of thrombolysis for acute myocardial infarction. Patients were randomized to one of four thrombolytic protocols. An angiographic substudy in 2,431 patients evaluated reperfusion, reocclusion and ventricular function. Effects of smoking were evaluated by logistic regression analysis after adjustment for age and gender. A mortality model evaluated the simultaneous effect of baseline characteristics on the prognostic importance of smoking. These processes were performed with data from both the main trial and the angiographic substudy; then angiographic factors (coronary anatomy, patency and ejection fraction) were added to the model. Smokers were significantly younger by a mean of 11 years) and had less comorbidity or severe coronary artery disease than nonsmokers. Nonsmokers had significantly higher hospital and 30-day mortality rates (9.9% and 10.3%, respectively) than smokers (3.7% vs. 4%, respectively, both p < 0.001) and more in-hospital complications. The unadjusted odds ratio for 30-day mortality in nonsmokers was 3.36 (95% confidence interval [CI] 2.08 to 5.41), 1.21 (95% CI 0.71 to 2.08) after adjustment for age and gender and 1.08 (95% CI 0.59 to 1.96) after adjustment for all clinical baseline characteristics. Smokers receiving thrombolysis for acute myocardial infarction presented 11 years earlier than nonsmokers, which generally accounted for their better outcome. When other differences in clinical and angiographic baseline factors and therapeutic responses were evaluated, no significant difference in mortality was seen between smokers and nonsmokers.


A High-Throughput Assay to Identify Inhibitors of the Apicoplast DNA Polymerase from Plasmodium falciparum.
Infection by Plasmodium falciparum is the leading cause of malaria in humans. The parasite contains a unique and essential plastid-like organelle called the apicoplast that, similar to the mitochondria and chloroplast, houses its own genome that must undergo replication and repair. The putative apicoplast replicative DNA polymerase, POM1, has no direct orthologs in mammals, making the P. falciparum POM1 an attractive antimalarial drug target. Here, we report on a fluorescent high-throughput DNA polymerase assay that relies on the ability of POM1 to perform strand-displacement synthesis through the stem of a DNA hairpin substrate, thereby separating a Cy3 dye from a quencher. Assay-validation experiments were performed using 384-well plates and resulted in a signal window of 7.90 and aZ' factor of 0.71. A pilot screen of a 2880-compound library identified 62 possible inhibitors that cause more than 50% inhibition of polymerase activity. The simplicity and statistical robustness of the assay suggest it is well suited for the screening of novel apicoplast polymerase inhibitors that may serve as lead compounds in antimalarial drug-discovery efforts.


Effects of changing reward on performance of the delayed spatial win-shift radial maze task in pedunculopontine tegmental nucleus lesioned rats.
Because it was designed to assess working memory, the delayed spatial win-shift (DSWS) radial maze task has been used to investigate the involvement of corticostriatal structures in executive processing. Excitotoxic lesions of the pedunculopontine tegmental nucleus (PPTg) produce profound deficits in performance of this task that are not accounted for by motor impairment. Thus, PPTg DSWS deficits are hypothesized to support a role for PPTg in complex cognitive processing. However, other studies indicate that the behaviour of PPTg lesioned rats varies depending on level of motivational excitement, assessed by the presence or absence of deprivation, or by manipulations of reward value. Since DSWS performance may also be affected by motivational dysfunction, the present experiment was conducted to examine the effects of post-surgical presentation of a more positive food reward (chocolate drops) on the DSWS retention performance of PPTg lesioned rats. Results confirmed a PPTg lesion deficit: lesioned rats made significantly more errors in both training and test phases, and made errors significantly earlier in their choice sequence in the test phase. Main effects of phase on number of errors indicated that the PPTg test phase deficit was not simply the result of a carry-over impairment from the training phase. PPTg rats receiving chocolate made significantly fewer errors than PPTg rats receiving food pellets. Results suggest that PPTg DSWS deficits are not the result of altered motivation or hedonic appreciation of reward value (or reward change) and therefore support the hypothesis of executive cognitive deficits in PPTg lesioned rats.


Meristem fate and bulbil formation in Titanotrichum (Gesneriaceae).
Titanotrichum oldhamii (a monotypic genus from Taiwan, Okinawa, and adjacent regions of China) has inflorescences bearing either showy yellow flowers or asexual bulbils. Asexual reproduction by bulbils is important in natural populations, and bulbil production increases in August and September at the end of the flowering season (which runs from June to the end of September). The bulbils are small (∼1-2.5 mm long) and numerous. They consist of a small portion of stem (bract-stem) topped by opposite storage bracts that enclose a minute apical meristem. A secondary root develops from the side of the bract-stem. The floral meristem of T. oldhamii has three possible fates: (1) bulbil formation, (2) flower formation, or (3) bracteose proliferation. Bracteose proliferation rarely occurs and appears to be a developmental transition between the bulbiliferous and racemose inflorescence forms. It is strongly reminiscent of the floricaula and squamosa mutants of Antirrhinum. In the bulbiliferous form a single floral primordium, which would normally produce one flower, gives rise to ∼50-70 bulbils by repeated subdivision of the meristem. This form of bulbil production appears to be unique to Titanotrichum. Occasionally a floral meristem divides, but the subdivision forms multiflowered units of up to four flowers rather than bulbils, suggesting that meristem fate is reversible up to the first or second meristem subdivision. In Titanotrichum, therefore, primordium fate is apparently not determined at inception but becomes irreversibly determined shortly after the appearance of developmental characteristics of the floral or bulbil pathway.


The Rice Genome Knowledgebase (RGKbase): an annotation database for rice comparative genomics and evolutionary biology.
Over the past 10 years, genomes of cultivated rice cultivars and their wild counterparts have been sequenced although most efforts are focused on genome assembly and annotation of two major cultivated rice (Oryza sativa L.) subspecies, 93-11 (indica) and Nipponbare (japonica). To integrate information from genome assemblies and annotations for better analysis and application, we now introduce a comparative rice genome database, the Rice Genome Knowledgebase (RGKbase, http://rgkbase.big.ac.cn/RGKbase/). RGKbase is built to have three major components: (i) integrated data curation for rice genomics and molecular biology, which includes genome sequence assemblies, transcriptomic and epigenomic data, genetic variations, quantitative trait loci (QTLs) and the relevant literature; (ii) User-friendly viewers, such as Gbrowse, GeneBrowse and Circos, for genome annotations and evolutionary dynamics and (iii) Bioinformatic tools for compositional and synteny analyses, gene family classifications, gene ontology terms and pathways and gene co-expression networks. RGKbase current includes data from five rice cultivars and species: Nipponbare (japonica), 93-11 (indica), PA64s (indica), the African rice (Oryza glaberrima) and a wild rice species (Oryza brachyantha). We are also constantly introducing new datasets from variety of public efforts, such as two recent releases-sequence data from ∼1000 rice varieties, which are mapped into the reference genome, yielding ample high-quality single-nucleotide polymorphisms and insertions-deletions.


Crossmodal correspondences between sounds and tastes.
In this article, the rapidly growing body of research that has been published recently on the topic of crossmodal correspondences that involve auditory and gustatory/flavor stimuli is critically reviewed. The evidence demonstrates that people reliably match different tastes/flavors to auditory stimuli varying in both their psychoacoustic (e.g., pitch) and musical (e.g., timbre) properties. In order to stimulate further progress in this relatively young research field, the present article aims at consolidating prior findings concerning specific auditory-gustatory mappings, whereby special attention is given to highlighting (1) any conflicts in the existing experimental evidence and (2) any potential caveats with regard to the most appropriate interpretation of prior studies. Next, potential mechanisms underlying auditory-gustatory crossmodal correspondences are discussed. Finally, a number of potentially fruitful avenues for future research are outlined.


miR-140 targeting CTSB signaling suppresses the mesenchymal transition and enhances temozolomide cytotoxicity in glioblastoma multiforme.
Temozolomide (TMZ) is a first-line chemotherapeutic agent used against glioblastoma multiforme (GBM), but this disease exhibits recurrence and high lethality. Therefore, it is critical to explore biomarkers which involve in drug resistance and can be represented as different therapeutic effects after a diagnosis. We attempted to investigate the underlying variably expressed genes that contribute to the formation of resistance to TMZ. We analyzed gene and microRNA (miR) data from GBM patients in The Cancer Genome Atlas (TCGA) database to identify genetic factors associated with poor TMZ efficacy. By conducting a gene set enrichment analysis (GSEA), the epithelial-to-mesenchymal transition (EMT) was associated with poor TMZ responses. To identify roles of microRNAs in regulating TMZ resistance, a differential microRNA analysis was performed in TMZ-treated GBM patients. Downregulation of miR-140 was significantly correlated with poor survival. By integrating TCGA transcriptomic data and genomics of drug sensitivity in cancer (GDSC), cathepsin B (CTSB) was inversely associated with miR-140 expression and poor TMZ efficacy. By a pan-cancer analysis, both miR-140 and CTSB were found to be prognostic factors in other cancer types. We also identified that CTSB was a direct target gene of miR-140. Overexpression of miR-140 reduced CTSB levels, enhanced TMZ cytotoxicity, suppressed the mesenchymal transition, and influenced CTSB-regulated tumor sphere formation and stemness marker expression. In contrast, overexpression of CTSB decreased TMZ-induced glioma cell death, promoted the mesenchymal transition, and attenuated miR-140-increased TMZ cytotoxicity. These findings provide novel targets to increase the therapeutic efficacy of TMZ against GBM.


Verteporfin-Loaded Poly(ethylene glycol)-Poly(beta-amino ester)-Poly(ethylene glycol) Triblock Micelles for Cancer Therapy.
Amphiphilic polymers can be used to form micelles to deliver water-insoluble drugs. A biodegradable poly(ethylene glycol) (PEG)-poly(beta-amino ester) (PBAE)-PEG triblock copolymer was developed that is useful for drug delivery. It was shown to successfully encapsulate and pH-dependently release a water-insoluble, small molecule anticancer drug, verteporfin. PEG-PBAE-PEG micelle morphology was also controlled through variations to the hydrophobicity of the central PBAE block of the copolymer in order to evade macrophage uptake. Spherical micelles were 50 nm in diameter, while filamentous micelles were 31 nm in width with an average aspect ratio of 20. When delivered to RAW 264.7 mouse macrophages, filamentous micelles exhibited a 89% drop in cellular uptake percentage and a 5.6-fold drop in normalized geometric mean cellular uptake compared to spherical micelles. This demonstrates the potential of high-aspect-ratio, anisotropically shaped PEG-PBAE-PEG micelles to evade macrophage-mediated clearance. Both spherical and filamentous micelles also showed therapeutic efficacy in human triple-negative breast cancer and small cell lung cancer cells without requiring photodynamic therapy to achieve an anticancer effect. Both spherical and filamentous micelles were more effective in killing lung cancer cells than breast cancer cells at equivalent verteporfin concentrations, while spherical micelles were shown to be more effective than filamentous micelles against both cancer cells. Spherical and filamentous micelles at 5 and 10 μM respective verteporfin concentration resulted in 100% cell killing of lung cancer cells, but both micelles required a higher verteporfin concentration of 20 μM to kill breast cancer cells at the levels of 80% and 50% respectively. This work demonstrates the potential of PEG-PBAE-PEG as a biodegradable, anisotropic drug delivery system as well as the in vitro use of verteporfin-loaded micelles for cancer therapy.


Improving monitoring after pancreas transplantation alone: fine-tuning of an old technique.
Graft survival after pancreas transplantation alone (PTA) is significantly poorer than graft survival after simultaneous pancreas kidney (SPK) and is particularly affected by difficulty in monitoring rejection. Exocrine bladder drainage allows assessment of pancreas graft function as urinary amylase (UA). However, standards for UA collection and interpretation are not well defined. In this study, 21 bladder-drained PTA recipients were monitored with daily values for UA and urine creatinine (Creat) concentration from post-transplant 10-mL samples and 24-h collections. Clinical events were documented and correlated to UA measurements. UA values were found to increase post-transplant until day 15, and large interpatient variability was noted (median 12 676 IU/L, range 668-60 369 IU/L). A strong correlation was found total 24-h UA production and spot UA/Creat ratio (r = 0.80, p < 0.001). UA/Creat ratio showed less variation during episodes of impaired renal function; therefore, urinary amylase baseline was defined as the median UA/Creat ratio after day 15. A > 25% decrease of UA predicted 9/13 (69%) events. We conclude that individual baselines should be set once the values have stabilized after 15 d post-transplant and that spot UA/Creat measures are reliable, patient friendly and indicate potential events after PTA.


Prostaglandins, the kidney, and hypertension.
Prostaglandins are part of the family of oxygenated metabolites of arachidonic acid known collectively as eicosanoids. While they are formed, act, and are inactivated locally and rarely circulate in plasma, they can affect blood flow in some tissues and so might contribute to the control of peripheral vascular resistance. Few studies have shown any derangement of total body prostaglandin synthesis or metabolism in hypertension, but increased renal synthesis of one prostanoid, thromboxane A2, has been noted in spontaneously hypertensive rats and some hypertensive humans. This potent vasoconstrictor may account for the increased renal vascular resistance and suppressed plasma renin activity seen in many patients with hypertension. Increased renal vascular resistance could increase the blood pressure directly as a component of total peripheral resistance or indirectly by increasing glomerular filtration fraction and tubular sodium reabsorption. Specific thromboxane synthesis inhibitors not only decrease renal thromboxane production but also increase renal vasodilator prostaglandin synthesis when prostaglandin synthesis is stimulated. This redirection of renal prostaglandin synthesis toward prostacyclin might be of benefit in correcting a fundamental renal defect in patients with hypertension.


Inhibition of p85, the non-catalytic subunit of phosphatidylinositol 3-kinase, exerts potent antitumor activity in human breast cancer cells.
The phosphoinositide 3-kinases (PI3Ks) are heterodimers consisting of the catalytic subunit p110 and the regulatory subunit p85. The PI3K/Akt pathway is strongly deregulated in breast cancer (BC) representing one of the mechanisms of resistance to therapies. Therefore, the identification of inhibitors of PI3K components represents one of the main goals to produce therapeutic agents. Here, we evaluated the efficacy of a phosphopeptide 1257 (P-1257) that targeting p85 strongly inhibits PI3K activity. We tested the effects of P-1257 administration in vitro and in vivo using BC cells expressing different levels of ErbB-2 and resistant or responsive to Trastuzumab. We demonstrated that inhibition of p85 activity by P-1257 induces cell death and sensitizes JIMT-1 and KPL-4 ErbB-2-overexpressing BC cells to Trastuzumab treatment. It is noteworthy that P-1257 delivery in vivo by electroporation or liposomes significantly inhibits the proliferation of tumor cells engrafted at subcutaneous and visceral sites. Overall, our data indicate that the p85 subunit is a valid target for therapeutic approaches and suggest that the structure of the peptide used in our study could be utilized for the development of novel drugs to apply in combination with therapies that fail to cure BCs with high PI3K activity.


Whole-genome resequencing allows detection of many rare LINE-1 insertion alleles in humans.
High-throughput sequencing has recently begun to revolutionize the study of structural variants in the genomes of humans and other species. More recently, this technology and others have been applied to the study of human retrotransposon insertion polymorphisms (RIPs), yielding an unprecedented catalog of common and rare variants due to insertional mutagenesis. At the same time, the 1000 Genomes Project has released an enormous amount of whole-genome sequence data. In this article, we present evidence for 1016 L1 insertions across all studies to date that are not represented in the reference human genome assembly, many of which appear to be specific to populations or groups of populations, particularly Africans. Additionally, a cross-comparison of several studies shows that, on average, 27% of surveyed nonreference insertions is present in only one study, indicating the low frequency of many RIPs.


Differences in cognitive processing? The role of verbal processes and mental effort in bilingual and monolingual children's planning performance.
Past research documents a bilingual advantage in the domain of executive functions (EFs). However, controversial debates have questioned the robustness of those behavioral differences. The current study aimed to better understand the underlying cognitive prerequisites in bilingual students as compared with monolingual students and focused on two processes: the role of verbal processes, on the one hand, and mental effort during task execution, on the other. The use of self-regulatory speech has been found to be related to performance in tasks requiring EFs. For bilinguals who have grown up with two language systems from an early age, those relations are not fully understood. Furthermore, results from neuroimaging studies have shown that bilinguals might exhibit less mental effort in EF tasks. We investigated both processes in German-speaking monolingual elementary school students (n = 33; Mage = 8.78 years) and German-Russian bilingual elementary school students (n = 34; Mage = 8.88 years) solving a planning task. Results showed that monolinguals were impaired by a verbal secondary task in comparison with a motor control condition, whereas bilinguals performed in both tasks at an equal level, indicating a differential role of self-regulatory speech in both language groups. Analyses of changes in pupil diameter revealed less mental effort during task execution for bilingual children as compared with monolingual children. The current study adds to the existing literature by supplying further evidence for cognitive differences between monolingual and bilingual children.


Association between circulating endostatin, hypertension duration, and hypertensive target-organ damage.
Our aim is to study associations between circulating endostatin, hypertension duration, and hypertensive target-organ damage. Long-term hypertension induces cardiovascular and renal remodeling. Circulating endostatin, a biologically active derivate of collagen XVIII, has been suggested to be a relevant marker for extracellular matrix turnover and remodeling in various diseases. However, the role of endostatin in hypertension and hypertensive target-organ damage is unclear. Serum endostatin was measured in 2 independent community-based cohorts: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS; women 51%; n = 812; mean age, 75 years) and the Uppsala Longitudinal Study of Adult Men (ULSAM; n=785; mean age, 77.6 years). Retrospective data on blood pressure measurements and antihypertensive medication (PIVUS >5 years, ULSAM >27 years), and cross-sectional data on echocardiographic left ventricular mass, endothelial function (endothelium-dependent vasodilation assessed by the invasive forearm model), and urinary albumin/creatinine ratio were available. In PIVUS, participants with ≥ 5 years of history of hypertension portrayed 0.42 SD (95% confidence interval, 0.23-0.61; P<0.001) higher serum endostatin, compared with that of normotensives. This association was replicated in ULSAM, in which participants with 27 years hypertension duration had the highest endostatin (0.57 SD higher; 95% confidence interval, 0.35-0.80; P<0.001). In addition, higher endostatin was associated with higher left ventricular mass, worsened endothelial function, and higher urinary albumin/creatinine ratio (P<0.03 for all) in participants with prevalent hypertension. Circulating endostatin is associated with the duration of hypertension, and vascular, myocardial, and renal indices of hypertensive target-organ damage. Further studies are warranted to assess the prognostic role of endostatin in individuals with hypertension.


Prevalence and antimicrobial susceptibilities of bacteria isolated from blood cultures of hospitalized patients in the United States in 2002.
Bloodstream infections are associated with significant patient morbidity and mortality. Antimicrobial susceptibility patterns should guide the choice of empiric antimicrobial regimens for patients with bacteremia. From January to December of 2002, 82,569 bacterial blood culture isolates were reported to The Surveillance Network (TSN) Database-USA by 268 laboratories. Susceptibility to relevant antibiotic compounds was analyzed using National Committee for Clinical Laboratory Standards guidelines. Coagulase-negative staphylococci (42.0%), Staphylococcus aureus (16.5%), Enterococcus faecalis (8.3%), Escherichia coli (7.2%), Klebsiella pneumoniae (3.6%), and Enterococcus faecium (3.5%) were the most frequently isolated bacteria from blood cultures, collectively accounting for >80% of isolates. In vitro susceptibility to expanded-spectrum beta-lactams such as ceftriaxone were high for oxacillin-susceptible coagulase-negative staphylococci (98.7%), oxacillin-susceptible S. aureus (99.8%), E. coli (97.3%), K. pneumoniae (93.3%), and Streptococcus pneumoniae (97.2%). Susceptibilities to fluoroquinolones were variable for K. pneumoniae (90.3-91.4%), E. coli (86.0-86.7%), oxacillin-susceptible S. aureus (84.0-89.4%), oxacillin-susceptible coagulase-negative staphylococci (72.7-82.7%), E. faecalis (52.1%), and E. faecium (11.3%). Combinations of antimicrobials are often prescribed as empiric therapy for bacteremia. Susceptibilities of all blood culture isolates to one or both agents in combinations of ceftriaxone, ceftazdime, cefepime, piperacillin-tazobactam or ciprofloxacin plus gentamicin were consistent (range, 74.8-76.3%) but lower than similar beta-lactam or ciprofloxacin combinations with vancomycin (range, 93.5-96.6%). Ongoing surveillance for antimicrobial susceptibility remains essential, and will enhance efforts to identify resistance and attempt to limit its spread.


Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families. Here we show that de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD. Moreover, 39% (49 of 126) of the most severe or disruptive de novo mutations map to a highly interconnected β-catenin/chromatin remodelling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes: CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3 and SCN1A. Combined with copy number variant (CNV) data, these results indicate extreme locus heterogeneity but also provide a target for future discovery, diagnostics and therapeutics.


Thermodynamic features and enthalpy relaxation in a metal-organic framework glass.
In this work, we explore the thermodynamic evolution in a melt-quenched metal-organic framework glass, formed from ZIF-62 upon heating to the melting point (Tm), and subsequent enthalpy relaxation. The temperature dependence of the difference in Gibbs free energy between the liquid and crystal states of ZIF-62 in the temperature range from the glass transition temperature (Tg) to Tm is found to be weaker than those of other types of glasses, e.g., metallic glasses. Additionally, we find that the stretched exponent of the enthalpy relaxation function in the glass varies significantly (β = 0.44-0.76) upon changing the extent of sub-Tg annealing, compared to metallic and oxide glasses with similar Tgs, suggesting a high degree of structural heterogeneity. Pair distribution function results suggest no significant structural changes during the sub-Tg relaxation in ZIF-62 glass.


Intrathecal administration of NTS1 agonists reverses nociceptive behaviors in a rat model of neuropathic pain.
Chronic neuropathic pain arising from peripheral nerve damage is a severe clinical issue where there is a major unmet medical need. We previously demonstrated that both neurotensin (NT) receptor subtypes 1 (NTS1) and 2 (NTS2) are involved in mediating the naloxone-insensitive antinociceptive effects of neurotensin in different analgesic tests including hotplate, tail-flick, and tonic pain. However, the role of these receptors in neuropathic pain management has been poorly investigated. In the present study, we therefore examined whether intrathecal delivery of NTS1 agonists was effective in reducing neuropathic pain symptoms in rats. Neuropathy was induced by sciatic nerve constriction (CCI model), and the development of mechanical allodynia and thermal hyperalgesia on the ipsi- and contralateral hind paws was examined 3, 7, 14, 21, and 28 days post-surgery. CCI-operated rats exhibited significant increases in thermal and mechanical hypersensitivities over a 28-day testing period. Spinal injection of NT to CCI rats alleviated the behavioral responses to radiant heat and mechanical stimuli, with a maximal reversal of 91% of allodynia at 6 μg/kg. Intrathecal administration of the NTS1-selective agonist, PD149163 (30-90 μg/kg) also produced potent anti-allodynic and anti-hyperalgesic effects in nerve-injured rats. Likewise, heat hyperalgesia and tactile allodynia produced by CCI of the sciatic nerve were fully reversed by the NTS1 agonist, NT69L (5-25 μg/kg). Altogether, these results support the idea that the NTS1 receptor subtype is involved in pain modulation, and the potential use of NTS1 agonists for the treatment of painful neuropathies.