Golimumab, a new human anti-tumor necrosis factor alpha antibody, administered intravenously in patients with active rheumatoid arthritis: Forty-eight-week efficacy and safety results of a phase III randomized, double-blind, placebo-controlled study.
To assess the efficacy and safety of intravenous administration of golimumab in patients with rheumatoid arthritis (RA). Adult patients with RA in whom disease activity was persistent despite treatment with methotrexate (MTX) at a dosage of 15-25 mg/week for > or = 4 weeks were randomized to receive intravenous infusions of placebo plus MTX or intravenous infusions of golimumab at a dose of 2 mg/kg or 4 mg/kg, with or without MTX, every 12 weeks through week 48. Patients with <20% improvement in the swollen and tender joint counts could enter early escape and receive additional active treatment (week 16) or could have their dose regimen adjusted (week 24). The primary end point was the proportion of patients achieving a 50% response according to the American College of Rheumatology improvement criteria (ACR50) at week 14. The primary study end point was not met (at week 14, an ACR50 response was observed in 21% of the patients treated with golimumab plus MTX compared with 13% of the patients treated with placebo plus MTX [P = 0.051]). By week 24, significantly more patients treated with golimumab plus MTX had achieved an ACR50 response. Differences in the proportion of patients achieving an ACR50 response between the group receiving golimumab monotherapy and the group receiving placebo plus MTX were not significant at either week 14 (16% versus 13%) or week 24 (10% versus 9%). At week 48, the proportions of patients achieving ACR20 and ACR50 responses were highest among those who had received golimumab 4 mg/kg plus MTX (70% and 48%, respectively). Concomitant treatment with MTX was associated with a lower incidence of antibodies to golimumab. The most commonly reported adverse events through week 48 were infections (48% of patients treated with golimumab with or without MTX and 41% of patients receiving placebo plus MTX). The primary end point was not met. However, intravenously administered golimumab plus MTX appears to have benefit in the longer-term reduction of RA signs/symptoms in MTX-resistant patients, with no unexpected safety concerns.


Joint estimation of genetic parameters for test-day somatic cell count and mastitis in the United Kingdom.
Genetic parameters were estimated in a joint analysis of log(e)-transformed somatic cell count (TSCC) with either mastitis as a binary trait (MAS) or the number of mastitis cases (NMAS) in Holstein-Friesian cows for the first 3 lactations using a random regression model. In addition, a multi-trait analysis of MAS and NMAS was also implemented. There were 67,175, 30,617, and 16,366 cows with records for TSCC, MAS, and NMAS in lactations 1, 2, and 3, respectively. The frequency of MAS was 14, 20, and 25% in lactations 1, 2, and 3 respectively. The model for TSCC included herd-test-day, age at calving and month of calving, fixed lactation curves nested with calving year groups, and random regressions with Legendre polynomials of order 2 for animal and permanent environmental effects. The model for MAS and NMAS included fixed herd-year-season, age at calving and month of calving, and random animal and permanent environmental effects. All analyses were carried out using Gibbs sampling. Estimates of mean daily heritability averaged over a 305-d lactation were 0.11, 0.14, and 0.15 for TSCC for lactations 1, 2, and 3, respectively. Corresponding heritability estimates for MAS were 0.05, 0.07, and 0.09. The heritabilities for NMAS were similar at 0.06, 0.07, and 0.12, respectively, for lactations 1, 2, and 3. The genetic correlations between lactations 1 and 2, 1 and 3, and 2 and 3 were 0.75, 0.64, and 0.92 for computed 305-d lactation TSCC; 0.55, 0.48, and 0.89 for MAS; and 0.62, 0.42, and 0.85 for NMAS, respectively. The genetic correlations between MAS and TSCC were positive and generally moderate to high. The genetic correlations between computed 305-d lactation TSCC and MAS were 0.53, 0.61, and 0.68 in lactations 1, 2, and 3, respectively. Similar corresponding genetic correlations were obtained between computed 305-d lactation TSCC and NMAS in the respective parities. Mastitis as a binary trait and NMAS in the same lactation were very highly correlated and were genetically the same trait. It is intended that the new parameters will be used in setting up a national evaluation system for the joint analysis of TSCC and MAS.


Phase Error Correction in Time-Averaged 3D Phase Contrast Magnetic Resonance Imaging of the Cerebral Vasculature.
Volume flow rate (VFR) measurements based on phase contrast (PC)-magnetic resonance (MR) imaging datasets have spatially varying bias due to eddy current induced phase errors. The purpose of this study was to assess the impact of phase errors in time averaged PC-MR imaging of the cerebral vasculature and explore the effects of three common correction schemes (local bias correction (LBC), local polynomial correction (LPC), and whole brain polynomial correction (WBPC)). Measurements of the eddy current induced phase error from a static phantom were first obtained. In thirty healthy human subjects, the methods were then assessed in background tissue to determine if local phase offsets could be removed. Finally, the techniques were used to correct VFR measurements in cerebral vessels and compared statistically. In the phantom, phase error was measured to be <2.1 ml/s per pixel and the bias was reduced with the correction schemes. In background tissue, the bias was significantly reduced, by 65.6% (LBC), 58.4% (LPC) and 47.7% (WBPC) (p < 0.001 across all schemes). Correction did not lead to significantly different VFR measurements in the vessels (p = 0.997). In the vessel measurements, the three correction schemes led to flow measurement differences of -0.04 ± 0.05 ml/s, 0.09 ± 0.16 ml/s, and -0.02 ± 0.06 ml/s. Although there was an improvement in background measurements with correction, there was no statistical difference between the three correction schemes (p = 0.242 in background and p = 0.738 in vessels). While eddy current induced phase errors can vary between hardware and sequence configurations, our results showed that the impact is small in a typical brain PC-MR protocol and does not have a significant effect on VFR measurements in cerebral vessels.


A reappraisal of generic bisphosphonates in osteoporosis.
The competitive price of generic bisphosphonates has had a marked effect on practice guidelines, but an increasing body of evidence suggests that they have more limited effectiveness than generally assumed. The purpose of this study is to review the impact of generic bisphosphonates on effectiveness in the treatment of osteoporosis. This study is a literature review. A substantial body of evidence indicates that many generic formulations of alendronate are more poorly tolerated than the proprietary preparations which results in significantly poorer adherence and thus effectiveness. Poorer effectiveness may result from faster disintegration times of many generics that increase the likelihood of adherence of particulate matter to the oesophageal mucosa. Unfortunately, market authorisation, based on the bioequivalence of generics with a proprietary formulation, does not take into account the potential concerns about safety. The poor adherence of many generic products has implications for guideline development, cost-effectiveness and impact of treatment on the burden of disease. The impact of generic bisphosphonates requires formal testing to re-evaluate their role in the management of osteoporosis.


Plus Disease in Retinopathy of Prematurity: Convolutional Neural Network Performance Using a Combined Neural Network and Feature Extraction Approach.
Retinopathy of prematurity (ROP), a leading cause of childhood blindness, is diagnosed by clinical ophthalmoscopic examinations or reading retinal images. Plus disease, defined as abnormal tortuosity and dilation of the posterior retinal blood vessels, is the most important feature to determine treatment-requiring ROP. We aimed to create a complete, publicly available and feature-extraction-based pipeline, I-ROP ASSIST, that achieves convolutional neural network (CNN)-like performance when diagnosing plus disease from retinal images. We developed two datasets containing 100 and 5512 posterior retinal images, respectively. After segmenting retinal vessels, we detected the vessel centerlines. Then, we extracted features relevant to ROP, including tortuosity and dilation measures, and used these features in the classifiers including logistic regression, support vector machine and neural networks to assess a severity score for the input. We tested our system with fivefold cross-validation and calculated the area under the curve (AUC) metric for each classifier and dataset. For predicting plus versus not-plus categories, we achieved 99% and 94% AUC on the first and second datasets, respectively. For predicting pre-plus or worse versus normal categories, we achieved 99% and 88% AUC on the first and second datasets, respectively. The CNN method achieved 98% and 94% for predicting two categories on the second dataset. Our system combining automatic retinal vessel segmentation, tracing, feature extraction and classification is able to diagnose plus disease in ROP with CNN-like performance. The high performance of I-ROP ASSIST suggests potential applications in automated and objective diagnosis of plus disease.


Helical optical projection tomography.
A new technique termed Helical Optical Projection Tomography (hOPT) has been developed with the aim to overcome some of the limitations of current 3D optical imaging techniques. hOPT is based on Optical Projection Tomography (OPT) with the major difference that there is a translation of the sample in the vertical direction during the image acquisition process, requiring a new approach to image reconstruction. Contrary to OPT, hOPT makes possible to obtain 3D-optical images of intact long samples without imposing limits on the sample length. This has been tested using hOPT to image long murine tissue samples such as spinal cords and large intestines. Moreover, 3D-reconstructed images of the colon of DSS-treated mice, a model for Inflammatory Bowel Disease, allowed the identification of the structural alterations. Finally, the geometry of the hOPT device facilitates the addition of a Selective Plane Illumination Microscopy (SPIM) arm, providing the possibility of delivering high resolution images of selected areas together with complete volumetric information.


Cell type- and activity-dependent extracellular correlates of intracellular spiking.
Despite decades of extracellular action potential (EAP) recordings monitoring brain activity, the biophysical origin and inherent variability of these signals remain enigmatic. We performed whole cell patch recordings of excitatory and inhibitory neurons in rat somatosensory cortex slice while positioning a silicon probe in their vicinity to concurrently record intra- and extracellular voltages for spike frequencies under 20 Hz. We characterize biophysical events and properties (intracellular spiking, extracellular resistivity, temporal jitter, etc.) related to EAP recordings at the single-neuron level in a layer-specific manner. Notably, EAP amplitude was found to decay as the inverse of distance between the soma and the recording electrode with similar (but not identical) resistivity across layers. Furthermore, we assessed a number of EAP features and their variability with spike activity: amplitude (but not temporal) features varied substantially (∼ 30-50% compared with mean) and nonmonotonically as a function of spike frequency and spike order. Such EAP variation only partly reflects intracellular somatic spike variability and points to the plethora of processes contributing to the EAP. Also, we show that the shape of the EAP waveform is qualitatively similar to the negative of the temporal derivative to the intracellular somatic voltage, as expected from theory. Finally, we tested to what extent EAPs can impact the lowpass-filtered part of extracellular recordings, the local field potential (LFP), typically associated with synaptic activity. We found that spiking of excitatory neurons can significantly impact the LFP at frequencies as low as 20 Hz. Our results question the common assertion that the LFP acts as proxy for synaptic activity.


The invariant chain forms complexes with class II major histocompatibility complex molecules and antigenic peptides "in vivo".
The binding of a chicken ovalbumin peptide (residues 323-339), Ova-(323-339), to I-Ad molecules was investigated in vitro and in vivo. By using antigenic peptides labeled either with a hapten or with fluorescein, complexes formed in vitro between I-Ad and antigenic peptides were detected by Western blot analysis with an antibody recognizing the hapten 7-nitrobenzo-2-oxa-1,3-diazole and by scanning gels for fluorescence emitted by fluoresceinated peptide. Both techniques reveal that Ova-(323-339) binds not only to I-Ad alpha/beta heterodimers and separated alpha and beta chains but also to complexes of higher molecular mass. Additional analysis shows that one of these additional complexes contains I-Ad heterodimers, antigenic peptides, and also invariant chain. To explore the physiological role of these complexes, cells were incubated with haptenated peptide and the I-Ad-peptide complexes formed in vivo were purified by affinity chromatography using hapten-specific antibody. The complexes formed migrate with a significantly higher apparent molecular mass than the alpha/beta heterodimers. A band at 180 kDa contained the alpha/beta heterodimer, the antigenic peptide, and the invariant chain. These results show that in vivo high molecular mass complexes formed by the I-Ad heterodimer and the invariant chain bind antigenic peptides.


Three-year follow-up of participants in a commercial weight loss program. Can you keep it off?
One third of Americans are obese, according to the 1988-1991 National Health and Nutrition Endpoint Survey III survey. Obesity increases the risk of death and a variety of chronic diseases. Numerous commercial weight loss programs demonstrate short-term success. To assess maintenance of weight loss achieved during dieting. We surveyed 192 participants in the Sandoz Nutrition (Sandoz Pharmaceuticals, Minneapolis, Minn) diet program approximately 3 years after participation. Initial date were supplied by the diet clinics and follow-up data, including weight at various points after the program, participation in other weight loss programs, and lifestyle variables, such as exercise, smoking, and television watching, were collected by a mailed questionnaire. On average, the group lost 22 kg during the diet program. After the follow-up period, the mean weight (mean, 102.6 kg) was only modestly less than the group's original weight at the start of the diet (mean, 105.9 kg). Twelve percent of the subjects maintained 75% of their weight loss after leaving the diet program, 57% maintained at least 5% of the loss, and 40% gained back more than they had lost during the diet. The frequency of exercise after the diet program was the strongest predictor of weight loss maintenance, while television viewing predicted a gain in weight. Given the apparent lack of substantial, long-term success at weight reduction, perhaps greater emphasis should be placed on prevention of obesity.


Molecular Phylogenetic Analysis, Trichothecene Chemotype Patterns, and Variation in Aggressiveness of Fusarium Isolates Causing Head Blight in Wheat.
Certain Fusarium species cause Fusarium head blight (FHB) in wheat and other small grains. Differences in characteristics of the pathogen species/isolates used in breeding programs may affect reaction of host genotypes, leading to erroneous results. To clarify differences among Fusarium isolates from different geographical zones, the phylogenetic, chemotypic, and pathogenic abilities of 58 isolates collected from three wheat-producing countries (Canada, Mexico, and Iran) were investigated. Phylogenetic relationships among the isolates were characterized using the Tri101 gene sequence. All Canadian and Iranian isolates clustered in one group and were identified as F. graminearum lineage 7 (=F. graminearum sensu stricto) within the F. graminearum (Fg) clade. The isolates from Mexico were identified as either F. graminearum lineage 3 (=Fusarium boothii) within the Fg clade or Fusarium crookwellense. A polymerase chain reaction assay based on the Tri12 gene identified three trichothecene chemotypes of 15-ADON, 3- ADON, and NIV, with 15-ADON being the most common. All F. boothii isolates from Mexico were of the 15-ADON chemotype, while all F. crookwellense isolates were determined to be NIV producers. While we did not find the NIV chemotype among the Canadian isolates, 25.6% of the Iranian isolates were determined to be NIV producers. High level of variation in aggressiveness was also observed among and within the species tested: F. graminearum sensu stricto isolates were the most aggressive, followed by those of F. boothii, and lastly by F. crookwellense. The differences observed among the isolates may explain why wheat lines/cultivars demonstrate different reactions to FHB in different geographical zones.


Mobility-assistive technology in progressive neuromuscular disease.
Mobility-assistive technologies allow patients with neuromuscular disease to interact with peers and the community. In children, they also serve to facilitate development. Lack of access to appropriate assistive technology, especially in regards to mobility, can have adverse developmental consequences. There are multiple options for mobility devices and methods for their control. These devices can be integrated with other electronics to facilitate the control of a variety of devices in the environment. The clinician should assess which devices are best based on the patient's, caregivers', and medical team's goals.


Suppression of time-dependent outward current in guinea pig ventricular myocytes. Actions of quinidine and amiodarone.
Prolongation of cardiac action potentials may mediate some of the arrhythmia-suppressing and arrhythmia-aggravating actions of antiarrhythmic agents. In this study, suppression of time-dependent outward current by quinidine and amiodarone was assessed in guinea pig ventricular myocytes. The net time-dependent outward current contained at least two components: a slowly activating, La(3+)-resistant delayed rectifier current (IK) and a rapidly activating, La(3+)-sensitive current. Quinidine block of total time-dependent outward current during clamp steps to positive potentials was relieved as a function of time, whereas that induced by amiodarone was enhanced. In contrast, at negative potentials, suppression of current, whereas amiodarone reduced IK but not the La(3+)-sensitive current, suggesting that differential block of the two components of time-dependent current underlies the distinct effects of the two agents. In contrast to these disparate effects on total time-dependent outward current, steady-state reduction of IK by both drugs increased at positive voltages and saturated at approximately +40 mV; the voltage dependence of block by quinidine (17% per decade, +10 to +30 mV) was steeper than that by amiodarone (5% per decade, +10 to +20 mV). Block by quinidine was time dependent at negative potentials: on stepping from +50 to -30 mV, block initially increased very rapidly, and subsequent deactivation of IK was slowed. This effect was not seen with amiodarone. At -80 mV, quinidine block was relieved with a time constant of 40 +/- 15 msec (n = 4, twin-pulse protocol). The effects of quinidine on IK were compatible with neither a purely voltage-dependent model of quinidine binding nor a model incorporating both voltage- and state-dependent binding of quinidine to delayed rectifier channels having only one open state. The voltage- and time-dependent features of quinidine block were well described by a model in which quinidine has greater affinity for one of two open states of the channel. We conclude that the effects of quinidine and amiodarone on time-dependent outward current reflects block of multiple channels. Quinidine block of IK was far more voltage dependent than that produced by amiodarone, suggesting the drugs act by different mechanisms.


Racial Experience as an Alternative Operationalization of Race.
The study of human variation is central to both social and biomedical sciences, but social and biomedical scientists diverge in how variation is theorized and operationalized. Race is especially problematic because it is a cultural concept that contains implicit and explicit understandings of how collective bodies differ. In this article, we propose an operationalization of race that addresses both racial experience and human biological diversity, placing them within the same ontological sphere. Furthermore, this approach can more effectively advance antiracist pedagogy and politics. We argue that human biological diversity does not have to be in opposition to constructivist notions of race. Rather, racial experience is emphasized as an embodied experience that is as real and as valid as biological variation. By focusing on both racial experience and biological diversity, it becomes more feasible to operationalize race to fruitfully inform the pedagogy and politics of antiracism. To do so, racial experience must be more broadly conceived and should not always equate to negative outcomes. With the recognition that racial experience has the potential to be something other than damaging, an antiracist anthropology can more effectively address issues pertaining to racial health disparities.


Expression of Na(+)-H+ exchanger isoforms NHE1 and NHE3 in kidney and blood cells of rabbit and rat.
Increased peripheral blood cell Na-H exchange (NHE) and erythrocyte Na-Li countertransport activity have been reported in hypertension and diabetic nephropathy and correlated with increased activity of the renal brush border Na-H exchanger. A relationship between cation exchange activities of blood cells and renal brush border membranes might exist if both were mediated by the same NHE isoform. We generated isoform-specific antibodies to compare the expression of NHE1 and NHE3 in peripheral blood cell membranes and renal cortical membrane vesicles. An NHE1-specific monoclonal antibody reacted with a 199- to 110-kD protein in basolateral membrane fractions isolated from rabbit and rat kidney. NHE1 protein expression was also detected in erythrocytes, platelets, and lymphocytes isolated from rabbit and rat. Two polyclonal antisera generated against nonoverlapping portions of NHE3 reacted with proteins of 82 and 85 kD in brush border membrane fractions isolated from rabbit and rat kidney, respectively, but failed to detect NHE3 expression in blood cells. These data do not support the hypothesis that Na-H exchanger of Na-Li countertransport in blood cells takes place via the renal brush border membrane NHE isoform, namely NHE3.


The α7-nicotinic acetylcholine receptor and MMP-2/-9 pathway mediate the proangiogenic effect of nicotine in human retinal endothelial cells.
Nicotine, the active component of cigarette smoke, has been found to stimulate angiogenesis in several experimental systems. In this study, the Matrigel duplex assay (Matrigel; BD Biosciences, Franklin Lakes, NJ) and the rat retinal explant assay were used to explore the molecular mechanisms underlying the proangiogenic effects of nicotine in endothelial cells. Western blot analysis was performed to determine the nicotinic acetylcholine receptor (nAChR) subtypes expressed on primary human retinal microvascular endothelial cells (HRMECs). The angiogenic effect of nicotine in the retina was evaluated with the duplex assay. The results obtained from the assay were confirmed by the rat retinal explant angiogenesis assay. ELISAs were used to measure MMP-2, -9, and -13 levels in HRMEC culture supernatants. The role of α7-nAChRs in nicotine-induced angiogenesis was examined by siRNA techniques. Nicotine-induced angiogenesis required nAChR function and was associated with the upregulation of MMP-2 and -9 in HRMECs. Specifically, α7-nAChRs mediated the stimulatory effects of nicotine on retinal angiogenesis and MMP levels. Treatment of HRMECs with α7-nAChR antagonists ablated nicotine-induced angiogenesis. The inhibitory actions of α7-nAChR antagonists correlated with the suppression of MMP-2 and -9 levels in HRMECs. The α7-nAChR is vital for the proangiogenic activity of nicotine. The α7-nAChRs expressed on HRMECs upregulate levels of MMP-2 and -9, which stimulate retinal angiogenesis. The data also suggest that α7-nAChR antagonists could be useful agents for the therapy of angiogenesis-related retinal diseases.


Spontaneous pregnancy loss in humans and exposure to arsenic in drinking water.
Maternal exposure to high concentrations of inorganic arsenic (iAs) in naturally contaminated drinking groundwater sources has been associated with an increased risk for the spontaneous loss of clinically recognized pregnancies in several epidemiologic studies. Whereas a large worldwide population depends on drinking groundwater sources with high levels of iAs contamination, in quantities exceeding 10 parts per billion (ppb), an even larger population is likely to be exposed to mild-moderate drinking groundwater iAs contamination, in quantities <10ppb. Only a single epidemiologic study to date has considered spontaneous pregnancy loss in association with consumption of drinking water with mild-moderate iAs contamination; the vast majority of published studies of spontaneous loss addressed populations with substantial exposure. The aim of this review is to evaluate the published literature to assess the plausibility for a causal association between exposure to iAs-contaminated drinking water and the spontaneous loss of clinically recognized pregnancy. In spite of numerous methodologic limitations resulting from circumstance or design, a consistent pattern of increased risk for loss is suggested by the epidemiologic literature. Moreover, these study results are corroborated by a large number of experimental studies, albeit usually conducted at concentrations exceeding that to which humans are exposed via contaminated drinking water. In this review, we discuss sources of human iAs exposure, highlight several experimental studies pertinent to a possible causal link between iAs and spontaneous pregnancy loss in humans, and provide a critical review of published epidemiologic studies of pregnancy loss and drinking water iAs exposures, and their limitations. Based on a review of the published literature, we recommend the future conduct of a two-stage comprehensive prospective study of low-moderate iAs drinking water exposure and spontaneous pregnancy loss.


In silico Screening and Heterologous Expression of a Polyethylene Terephthalate Hydrolase (PETase)-Like Enzyme (SM14est) With Polycaprolactone (PCL)-Degrading Activity, From the Marine Sponge-Derived Strain Streptomyces sp. SM14.
Plastics, such as the polyethylene terephthalate (PET), are widely used for various industrial applications, due to their physicochemical properties which are particularly useful in the packaging industry. However, due to improper plastic waste management and difficulties in recycling, post-consumer plastic waste has become a pressing issue for both the environment and for human health. Hence, novel technologies and methods of processing plastic waste are required to address these issues. Enzymatic-assisted hydrolysis of synthetic polymers has been proposed as a potentially more efficient and environment-friendly alternative to the currently employed methods. Recently, a number of PET hydrolases have been described, and in particular a PETase derived from Ideonella sakaiensis 201-F6 (IsPETase), which appears to be the most efficient and substrate-specific bacterial PET hydrolase enzyme discovered to date. In order to further investigate this class of PETase-like enzymes, we employed an in silico-based screening approach on the biotechnologically relevant genus Streptomyces, including terrestrial and marine isolates; in a search for potential PETase homologs. From a total of 52 genomes analyzed, we were able to identify three potential PETase-like enzymes, all of which were derived from marine-sponge associated Streptomyces isolates. A candidate PETase-like gene (SM14est) was identified in Streptomyces sp. SM14. Further in silico characterization of the SM14est protein sequence and its predicted three-dimensional structure were performed and compared to the well-characterized IsPETase. Both the serine hydrolase motif Gly-x1-Ser-x2-Gly and the catalytic triad Ser, Asp, His are conserved in both sequences. Molecular docking experiments indicated that the SM14est enzyme possessed the capacity to bind plastics as substrates. Finally, polyesterase activity was confirmed using a polycaprolactone (PCL) plate clearing assay which is a model substrate for the degradation of plastics; following heterologous expression of SM14est in Escherichia coli, with secretion being facilitated by the native Streptomyces signal peptide. These findings provide further insights into this important class of PETase-like enzymes.


High specificity of line-immunoassay based algorithms for recent HIV-1 infection independent of viral subtype and stage of disease.
Serologic testing algorithms for recent HIV seroconversion (STARHS) provide important information for HIV surveillance. We have shown that a patient's antibody reaction in a confirmatory line immunoassay (INNO-LIA HIV I/II Score, Innogenetics) provides information on the duration of infection. Here, we sought to further investigate the diagnostic specificity of various Inno-Lia algorithms and to identify factors affecting it. Plasma samples of 714 selected patients of the Swiss HIV Cohort Study infected for longer than 12 months and representing all viral clades and stages of chronic HIV-1 infection were tested blindly by Inno-Lia and classified as either incident (up to 12 m) or older infection by 24 different algorithms. Of the total, 524 patients received HAART, 308 had HIV-1 RNA below 50 copies/mL, and 620 were infected by a HIV-1 non-B clade. Using logistic regression analysis we evaluated factors that might affect the specificity of these algorithms. HIV-1 RNA < 50 copies/mL was associated with significantly lower reactivity to all five HIV-1 antigens of the Inno-Lia and impaired specificity of most algorithms. Among 412 patients either untreated or with HIV-1 RNA ≥ 50 copies/mL despite HAART, the median specificity of the algorithms was 96.5% (range 92.0-100%). The only factor that significantly promoted false-incident results in this group was age, with false-incident results increasing by a few percent per additional year. HIV-1 clade, HIV-1 RNA, CD4 percentage, sex, disease stage, and testing modalities exhibited no significance. Results were similar among 190 untreated patients. The specificity of most Inno-Lia algorithms was high and not affected by HIV-1 variability, advanced disease and other factors promoting false-recent results in other STARHS. Specificity should be good in any group of untreated HIV-1 patients.


Effect of Yoga on Lipid Profile and C-reactive Protein in Women.
Few scientific studies have been conducted about the effect of yoga on biochemical variables such as total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), and C-reactive protein (CRP) to lay a scientific foundation regarding benefits of yoga, but its effect is not clearly detected yet. This study was conducted to assess the effect of yoga on lipid profile and CRP in women. This research was designed as an interventional study. After reviewing inclusion and exclusion criteria, selected biochemical variables such as TC, HDL-C, LDL-C, TG, and CRP were measured for each participant. Yoga instruction was done three times a week for 26 weeks by an experienced yoga instructor. After 26 weeks of yoga intervention, the above-mentioned dependent variables were assessed. SPSS Ver. 16 was used for data analysis. After a 26-week follow-up for participants, only 24 women had the necessary criteria to be included in the study. The mean TG was 157.33 ± 68.416 mg/dL and 134.33 ± 58.80 mg/dL before and after the intervention (P = 0.108), respectively. The mean TC was 234.83 ± 48.47 mg/dL and 183.33 ± 55.09 mg/dL before and after the intervention (P = 0.014), respectively. The mean HDL-C was 31.58 ± 14.22 mg/dL and 38.25 ± 13.5 mg/dL before and after the intervention (P = 0.118), respectively. The mean LDL-C was 171.75 ± 42.69 mg/dL and 142.91 ± 36.4 mg/dL before and after the intervention (P = 0.030), respectively. The mean CRP was 0.57 ± 0.22 mg/L and 0.71 ± 0.77 mg/L before and after the intervention (P = 0.779), respectively. The result showed that yoga reduced TC and LDL-C significantly, but had no significant effect on TG, HDL-C, and CRP.


Developmental differences in the shear stress-induced expression of endothelial NO synthase: changing role of AP-1.
Endothelial nitric oxide synthase (eNOS) mRNA and protein levels increase during late gestation and then decrease postnatally in sheep lung parenchyma. The increase in fluid shear stress at birth, resulting from increased pulmonary blood flow, is an important mediator of postnatal eNOS gene expression. Our objective was to identify factors stimulating eNOS expression in pulmonary arterial endothelial cells (PAEC) in response to shear stress and to determine if these factors are developmentally regulated. PAEC were isolated from fetal lambs and adult sheep. Transcriptional activity from a 1,600-bp eNOS promoter fragment increased in both fetal and adult PAEC exposed to 8 h of shear stress. Conversely, activity driven from an 840-bp promoter fragment containing a putative activator protein (AP)-1 binding site was increased only in fetal PAEC. This increase was completely abolished in an identical construct containing a mutant AP-1 sequence. The AP-1 protein c-Jun was localized to the cytosol in static adult PAEC and to the nucleus in static fetal PAEC. After shear, c-Jun was nuclear localized in both cell types. However, transcriptionally active phosphorylated c-Jun was elevated only in the nuclei of sheared fetal PAEC. Resting levels of eNOS and NO were 2- and 20-fold higher, respectively, in fetal cells. Shear increased eNOS and NO in both cell types: levels were approximately 2.5-fold higher in fetal PAEC. Phosphorylation of Akt and eNOS was evident in sheared fetal but not adult PAEC. We have therefore identified mechanisms of eNOS regulation at the transcriptional level and to be enzyme activation specific to the fetal pulmonary arterial circulation.


The Impact of Extracorporeal Shock Wave Therapy and Dry Needling Combination on Pain and Functionality in the Patients Diagnosed with Plantar Fasciitis.
This study aimed to evaluate the efficiency of extracorporeal shock wave therapy (ESWT) and dry needling (DN) combination on pain and functionality in plantar fasciitis. Forty patients who were clinically diagnosed with plantar fasciitis were included in the study. The patients were randomly divided into 2 groups. The ESWT-DN group was applied 3 sessions of ESWT to plantar fascia and DN to the trigger points in the gastrosoleus muscles. The ESWT group was applied only ESWT treatment to plantar fascia. We used visual analog scale (VAS) for pain and a pressure algometer for pressure pain threshold. The functionality of the patients was evaluated with Foot Function Index (FFI). Also, maximum painless standing time and maximum painless walking distance were recorded. All assessments were repeated twice; first, pretreatment and second 1 month after the treatment. In both groups, there were statistically significant improvements in VAS, pressure pain threshold, maximum painless standing time, maximum painless walking distance, and FFI's pain, disability, and activity limitation subscales scores (p ≤ .001). In intergroup comparison; it was showed that VAS scores, maximum painless standing time (p = .002), maximum painless walking distance (p ≤ .001), and FFI pain subscale scores (p = .034) were statistically superior in the ESWT-DN group. There was no statistically difference between the groups in pressure pain threshold (p = .132), FFI disability (p = .081), and FFI activity limitation subscale (p = .226) scores. ESWT and DN combination therapy in plantar fasciitis was seen to be superior in the pain scores. Further studies with larger patients' groups and longer term results of this combination are needed for a better comparison.


Gender differences in public perceptions on National Health Insurance.
Implementation of National Health Insurance (NHI) commenced recently. With the promise of addressing drastic inequalities in the health sector, NHI has the potential to positively transform the health system . In particular, NHI could have a significant positive impact on females, who are disadvantaged under the current system, with higher rates of poor health and lower rates of medical scheme membership compared with males. Despite NHI's transformative potential, however, the public discourse on NHI as portrayed in the media suggests that it is an unpopular policy. The evidence presented in this paper is to the contrary. To assess the general public's opinion on NHI and to explore gender differences in perceptions. This paper reports on findings from a 2010 cross-sectional nationally representative survey of the South African population that assessed social attitudes, including perceptions on NHI. Sex-disaggregated data were analysed in SPSS version 20. There is broad public acceptance of NHI, indicating that an overwhelming majority of South Africans would prefer an NHI system to the current two-tiered system. Support for NHI has increased since similar studies in 2005 and 2008, with the simultaneous growth of public discourse on the policy. More females than males support NHI, reflecting the potential of the NHI system to have a positive impact on gender equality and the health of women and girls.


Exergaming-Based Dexterity Training in Persons With Parkinson Disease: A Pilot Feasibility Study.
Many individuals with Parkinson disease (PD) suffer from impaired dexterity, which impacts activities of daily living and quality of life. Exergaming, video game-based training with augmented virtual reality, may have value for improving function. The aim of the present pilot study was to comprehensively evaluate the feasibility of a dexterity training program using exergaming, in individuals with PD. Ten participants with PD (aged between 55 and 75 years, Hoehn and Yahr stages II-IV) trained over a period of 4 weeks, twice a week for 30 minutes. Baseline (T0) and postintervention (T1) assessments were done. Primary outcomes with respect to feasibility were the adherence rate, open-end questions, the level of participation (Pittsburgh Rehabilitation Participation Scale), and the usability (System Usability Scale). Dexterous function was measured with the Nine-Hole Peg Test and the Dexterity Questionnaire-24. Upper limb motor impairment was assessed by a modified version of the Movement Disorders Society Unified Parkinson's Disease Rating Scale III. Finally, quality of life was assessed by the 39-item Parkinson's Disease Questionnaire (PDQ-39). Adherence rate was 99%, motivation increased significantly from 3.9 to 4.8 (Pittsburgh Rehabilitation Participation Scale, P = 0.03), and system usability of the exergaming system was acceptable to very good. Regarding potential efficacy, participants with impaired dexterity at T0 significantly improved in the Nine-Hole Peg Test and the PDQ-39. The outcomes of this pilot study suggest that exergaming is feasible and has potential to improve dexterity in individuals with PD. Its efficacy should be investigated in a properly powered randomized controlled trial.Video Abstract available for more insights from the authors (see Supplemental Digital Content 1, available at: http://links.lww.com/JNPT/A270).


Tophus burden reduction with pegloticase: results from phase 3 randomized trials and open-label extension in patients with chronic gout refractory to conventional therapy.
Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy. Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR. Among 212 patients randomized in the RCTs, 155 (73%) had ≥ 1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo). Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy. NCT00325195, NCT01356498.


Prolonged sitting time links to subclinical atherosclerosis.
This study investigates the association between daily sitting time and subclinical atherosclerosis by using coronary computed tomography angiography (CCTA). The study enrolled 203 subjects (age 57.6 ± 8.8 years) who underwent CCTA at annual medical checkups. Sitting time was categorized as < 5 hours/day (short), 5 to 9 hours/day (moderate) and ≥10 hours/d (long). We analyzed the coronary calcium score, plaque characteristics, and severity of coronary artery stenosis, including the segment involvement score (SIS) and segment stenosis score (SSS). Subjects with longer sitting times tended to be male gender and have lower levels of high-density lipoprotein cholesterol (p for trend < 0.05). In addition, those with longer sitting time had higher SIS (1.2 ± 1.5 vs. 1.6 ± 2.1 vs. 2.3 ± 2.0 for short, moderate, and long sitting time, respectively) (p for trend = 0.015) and SSS (1.4 ± 2.0 vs. 1.9 ± 2.7 vs. 2.7 ± 2.6) (p for trend = 0.015), suggesting longer sitting time-correlated with the severity of coronary atherosclerosis. When considering the coronary plaque patterns, subjects with shorter sitting time (<5 hours/d) tended to have more calcified plaque and subjects with longer sitting time (≥10 hours/d) had more mixed plaque (p for trend = 0.018). After adjusting for age, gender, comorbidities, body mass index, and lipid profiles, increased sitting time was independently associated with the presence of mixed plaque, suggesting longer sitting time may be associated with higher risk of the formation of vulnerable plaque. Longer sitting time was linked to the severity of subclinical atherosclerosis and the presence of high-risk vulnerable plaque in the general population.


Genetic and physiological analysis of conjugation in Streptococcus faecalis.
In an effort to elucidate the mechanisms of conjugal plasmid transfer in Streptococcus faecalis, a genetic analysis of the sex pheromone-dependent tetracycline resistance plasmid pCF-10 was initiated. Rare transconjugants obtained from short matings with wild-type donors not exposed to sex pheromones were screened for increased donor potential in a subsequent mating. From this screening, a mutant plasmid, designated pCF-11, whose transfer functions are expressed in the absence of pheromone induction was isolated. Cells carrying pCF-11 spontaneously clump when grown in broth culture but do not excrete sex pheromones active against wild-type donors. In the course of initial experiments, it was observed that physiological conditions could affect plasmid transfer frequency. Therefore, a set of standardized optimal mating conditions was defined. The experiments carried out to determine these conditions revealed that a transient increase in transfer frequency of about 2 order of magnitude occurred in early-exponential-phase donor cells. This peak of activity is independent of sex pheromone response, since it was observed with induced or uninduced donor cells carrying either pCF-11 or pCF-10.


Changes in the distribution of mechanically dependent plants along a gradient of past hurricane impact.
The severity of the effects that large disturbance events such as hurricanes can have on the forest canopy and the associated mechanically dependent plant community (epiphytes, climbers, etc.) is dependent on the frequency and intensity of the disturbance events. Here we investigate the effects of different structural and environmental properties of the host trees and previously modelled past hurricanes on dependent plants in Cusuco National Park, Honduras. Tree-climbing methods were employed to sample different dependent life-forms in ten 150 × 150 m plots. We identified 7094 individuals of dependent plants from 214 different species. For holo- and hemi-epiphytes, we found that diversity was significantly negatively related to past hurricane impact. The abundance of dependent plants was greatly influenced by their position in tree canopy and hurricane disturbance regimes. The relationship between abundance and mean branch height shifts across a gradient of hurricane impact (from negative to positive), which might result from a combination of changes in abundance of individual species and composition of the dependent flora across sites. Mechanically dependent plants also responded to different structural and environmental conditions along individual branches. The variables that explained much of the community differences of life-forms and families among branches were branch surface area and bryophyte cover. The factors that explained most variation at a plot level were mean vapour pressure deficit and elevation. At the level of the individual tree, the most important factors were canopy openness and past hurricane impact. We believe that more emphasis needs to be placed on the effects that past disturbance events have on mechanically dependent plant communities, particularly in areas that are prone to catastrophic perturbations.


Are certain multicenter randomized clinical trial structures misleading clinical and policy decisions?
Multicenter studies involving randomized clinical trials (RCTs) may have different structures. We discuss four general types. The first two, an "ideal" multicenter RCT and decentralized multicenter collaborative RCTs, we feel are, in different circumstances, highly recommended approaches. The other two, the multicenter RCT that ignores site differences and centralized multicenter collaborative RCTs, we argue, are not only not cost-effective but may also produce misleading results, thus impeding scientific progress and possibly putting patients at unnecessary risk.


Postoperative serum proteomic profiles may predict recurrence-free survival in high-risk primary breast cancer.
Better breast cancer prognostication may improve selection of patients for adjuvant therapy. We conducted a retrospective longitudinal study in which we investigated sera of high-risk primary breast cancer patients, to search for proteins predictive of recurrence-free survival. Sera of 82 breast cancer patients obtained after surgery, but prior to the administration of adjuvant therapy, were fractionated using anion-exchange chromatography, to facilitate the detection of the low-abundant serum peptides. Selected fractions were subsequently analysed by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS), and the resulting protein profiles were searched for prognostic markers by appropriate bioinformatics tools. Four peak clusters (i.e. m/z 3073, m/z 3274, m/z 4405 and m/z 7973) were found to bear significant prognostic value (P ≤ 0.01). The m/z 3274 candidate marker was structurally identified as inter-alpha-trypsin inhibitor heavy chain 4 fragment(658-688) in serum. Except for the m/z 7973 peak cluster, these peaks remained independently associated with recurrence-free survival upon multivariate Cox regression analysis, including clinical parameters of known prognostic value in this study population. Investigation of the postoperative serum proteome by, e.g., anion-exchange fractionation followed by SELDI-TOF MS analysis is promising for the detection of novel prognostic factors. However, regarding the rather limited study population, validation of these results by analysis of independent study populations is warranted to assess the true clinical applicability of discovered prognostic markers. In addition, structural identification of the other markers will aid in elucidation of their role in breast cancer prognosis, as well as enable development of absolute quantitative assays.


Electrocardiographic response to enzyme replacement therapy for Pompe disease.
Electrocardiogram (ECG) abnormalities are universal in infantile Pompe disease or glycogen storage disease type II, a fatal genetic muscle disorder caused by deficiency of acid alpha-glucosidase (GAA). Hallmarks of this disease include a shortened PR interval, an increased QT dispersion (QTd), and large left ventricular (LV) voltages. We evaluated the effect of recombinant human GAA (rhGAA) enzyme replacement therapy (ERT) on these ECG parameters in patients with infantile-onset Pompe disease. A total of 134 ECGs were evaluated from 19 patients (5 females and 14 males) with a median age of 5.5 months at the time of enrollment in open-label clinical trials exploring the safety and efficacy of ERT at a single center from 1999 to 2004. rhGAA was purified from genetically engineered Chinese hamster ovary cells overproducing GAA and infused intravenously at doses ranging from 10 mg/kg per week to 20 to 40 mg/kg every 2 weeks in patients with infantile-onset Pompe disease. The PR interval, QTd (longest to shortest QT), and LV voltage (SV1 + RV6) were blindly determined by two independent observers. The median follow-up period was 6 months (range 2-30 months). The PR interval lengthened from 83 (42-110) ms to 107 (95-130) ms (P < .001), and the QTd decreased from 83 (40-125) ms to 53 (20-80) ms (P = .003). There were significant decreases in LV voltage (67 [17-83] mV vs. 48 [18-77] mV, P = .03), which correlated with decrease in LV mass on two-dimensional echocardiogram. There was no evident change in the QTc interval (429 [390-480] ms vs. 413 [370-450] ms, P = not significant). rhGAA ERT for infantile Pompe disease results in an increase in PR interval and a decrease in both the QTd and the LV voltage. These results suggest that these ECG parameters may be useful markers of the severity of cardiac disease and the response to ERT treatment in patients with infantile Pompe disease.


Genome sequencing and analysis of the first complete genome of Lactobacillus kunkeei strain MP2, an Apis mellifera gut isolate.
Background. The honey bee (Apis mellifera) is the most important pollinator in agriculture worldwide. However, the number of honey bees has fallen significantly since 2006, becoming a huge ecological problem nowadays. The principal cause is CCD, or Colony Collapse Disorder, characterized by the seemingly spontaneous abandonment of hives by their workers. One of the characteristics of CCD in honey bees is the alteration of the bacterial communities in their gastrointestinal tract, mainly due to the decrease of Firmicutes populations, such as the Lactobacilli. At this time, the causes of these alterations remain unknown. We recently isolated a strain of Lactobacillus kunkeei (L. kunkeei strain MP2) from the gut of Chilean honey bees. L. kunkeei, is one of the most commonly isolated bacterium from the honey bee gut and is highly versatile in different ecological niches. In this study, we aimed to elucidate in detail, the L. kunkeei genetic background and perform a comparative genome analysis with other Lactobacillus species. Methods. L. kunkeei MP2 was originally isolated from the guts of Chilean A. mellifera individuals. Genome sequencing was done using Pacific Biosciences single-molecule real-time sequencing technology. De novo assembly was performed using Celera assembler. The genome was annotated using Prokka, and functional information was added using the EggNOG 3.1 database. In addition, genomic islands were predicted using IslandViewer, and pro-phage sequences using PHAST. Comparisons between L. kunkeei MP2 with other L. kunkeei, and Lactobacillus strains were done using Roary. Results. The complete genome of L. kunkeei MP2 comprises one circular chromosome of 1,614,522 nt. with a GC content of 36,9%. Pangenome analysis with 16 L. kunkeei strains, identified 113 unique genes, most of them related to phage insertions. A large and unique region of L. kunkeei MP2 genome contains several genes that encode for phage structural protein and replication components. Comparative analysis of MP2 with other Lactobacillus species, identified several unique genes of L. kunkeei MP2 related with metabolism, biofilm generation, survival under stress conditions, and mobile genetic elements (MGEs). Discussion. The presence of multiple mobile genetic elements, including phage sequences, suggest a high degree of genetic variability in L. kunkeei. Its versatility and ability to survive in different ecological niches (bee guts, flowers, fruits among others) could be given by its genetic capacity to change and adapt to different environments. L. kunkeei could be a new source of Lactobacillus with beneficial properties. Indeed, L. kunkeei MP2 could play an important role in honey bee nutrition through the synthesis of components as isoprenoids.


The impact of policies to reduce blood glucose test strip utilization and costs in Canada.
Several strategies have been proposed to manage the utilization of blood glucose test strips (BGTS) in Canada; however their potential impacts on utilization and costs of publically funded test strips are unknown. We investigated the impact of three potential policies that would restrict the number of test strips reimbursed by the public drug plans in Ontario and British Columbia (BC), and incorporated negotiated price reductions. These policies were based on recommendations from the Canadian Agency for Drugs and Technologies in Health, a briefing document by the Canadian Diabetes Association, and a new policy introduced by the Ontario Ministry of Health and Long-Term Care. BGTS utilization rates were assessed in two cross-sectional analyses among adults aged 18 years or older in BC and 65 or older in Ontario who received publicly-funded BGTS between January 2004 and December 2012. We modeled the 5-year utilization and cost implications of the three policies using time-series analysis. In 2012, there were 317,130 test strip recipients in Ontario and 136,659 recipients in BC, at a cost of $104.4 million and $22.6 million respectively. Under the scenarios of reduced BGTS quantities, 5-year cost savings ranged between $98.8 million (18.2% reduction) and $224.1 million (41.4% reduction) in Ontario and between $23.1 million (19.2% reduction) and $51.1 million (42.4% reduction) in BC. Price reductions of 15% resulted in annual savings of $14.4 million (13.7% reduction) in Ontario and $3.4 million (14.1% reduction) in BC. Policies that align with evidence and expert guidance could impart substantial cost savings in multiple jurisdictions despite different public drug plans.


Does health differ between participants and non-participants in the MRI-HUNT study, a population based neuroimaging study? The Nord-Trøndelag health studies 1984-2009.
Bias with regard to participation in epidemiological studies can have a large impact on the generalizability of results. Our aim was to investigate the direction and magnitude of potential bias by comparing health-related factors among participants and non-participants in a MRI-study based on HUNT, a large Norwegian health survey. Of 14,033 individuals aged 50-65, who had participated in all three large public health surveys within the Norwegian county of Nord-Trøndelag (HUNT 1, 2 and 3), 1,560 who lived within 45 minutes of travel from the city of Levanger were invited to a MRI study (MRI-HUNT). The sample of participants in MRI-HUNT (n = 1,006) were compared with those who were invited but did not participate (n = 554) and with those who were eligible but not invited (n = 12,473), using univariate analyses and logistic regression analyses adjusting for age and education level. Self-reported health did not differ between the three groups, but participants had a higher education level and were somewhat younger than the two other groups. In the adjusted multivariate analyses, obesity was consistently less prevalent among participants. Significant differences in blood pressure and cholesterol were also found. This is the first large population-based study comparing participants and non-participants in an MRI study with regard to general health. The groups were not widely different, but participants had a higher level of education, and were less likely to be obese and have hypertension, and were slightly younger than non-participants. The observed differences between participants and non-invited individuals are probably partly explained by the inclusion criterion that participants had to live within 45 minutes of transport to where the MRI examination took place. One will expect that the participants have somewhat less brain morphological changes related to cardiovascular risk factors than the general population. Such consequences underline the crucial importance of evaluation of non-participants in MRI studies.


The effects of message recipients' power before and after persuasion: a self-validation analysis.
In the present research, the authors examined the effect of a message recipient's power on attitude change and introduced a new mechanism by which power can affect social judgment. In line with prior research that suggested a link between power and approach tendencies, the authors hypothesized that having power increases confidence relative to being powerless. After demonstrating this link in Experiment 1, in 4 additional studies, they examined the role of power in persuasion as a function of when power is infused into the persuasion process. On the basis of the idea that power validates whatever mental content is accessible, they hypothesized that power would have different effects on persuasion depending on when power was induced. Specifically, the authors predicted that making people feel powerful prior to a message would validate their existing views and thus reduce the perceived need to attend to subsequent information. However, it was hypothesized that inducing power after a message has been processed would validate one's recently generated thoughts and thus influence the extent to which people rely upon their thoughts in determining their attitudes.


Application of Modeling Approaches to Explore Vaccine Adjuvant Mode-of-Action.
Novel adjuvant technologies have a key role in the development of next-generation vaccines, due to their capacity to modulate the duration, strength and quality of the immune response. The AS01 adjuvant is used in the malaria vaccine RTS,S/AS01 and in the licensed herpes-zoster vaccine (Shingrix) where the vaccine has proven its ability to generate protective responses with both robust humoral and T-cell responses. For many years, animal models have provided insights into adjuvant mode-of-action (MoA), generally through investigating individual genes or proteins. Furthermore, modeling and simulation techniques can be utilized to integrate a variety of different data types; ranging from serum biomarkers to large scale "omics" datasets. In this perspective we present a framework to create a holistic integration of pre-clinical datasets and immunological literature in order to develop an evidence-based hypothesis of AS01 adjuvant MoA, creating a unified view of multiple experiments. Furthermore, we highlight how holistic systems-knowledge can serve as a basis for the construction of models and simulations supporting exploration of key questions surrounding adjuvant MoA. Using the Systems-Biology-Graphical-Notation, a tool for graphical representation of biological processes, we have captured high-level cellular behaviors and interactions, and cytokine dynamics during the early immune response, which are substantiated by a series of diagrams detailing cellular dynamics. Through explicitly describing AS01 MoA we have built a consensus of understanding across multiple experiments, and so we present a framework to integrate modeling approaches into exploring adjuvant MoA, in order to guide experimental design, interpret results and inform rational design of vaccines.


High Levels of Epstein-Barr Virus Nuclear Antigen-1-Specific Antibodies and Infectious Mononucleosis Act Both Independently and Synergistically to Increase Multiple Sclerosis Risk.
Objective: Elevated levels of anti-EBNA-1 antibodies and infectious mononucleosis (IM) history have consistently been associated with multiple sclerosis (MS) risk. We aimed to study whether these aspects of Epstein-Barr virus (EBV) infection represent separate risk factors for MS and whether they both interact with MS-associated HLA genes in disease development. Methods: Two Swedish-population-based case-control studies were used, comprising 5,316 cases and 5,431 matched controls. Subjects with different HLA alleles, EBNA-1, and IM status were compared regarding MS risk by calculating odds ratios (OR) with 95% confidence intervals (CI) employing logistic regression. Causal mediation analysis was used to assess to what extent the relationship between IM history and MS risk was mediated by high anti-EBNA-1 antibody levels and vice versa. Results: The causal mediation analysis revealed that both aspects of EBV infection mainly act directly on MS risk. The direct effect of elevated anti-EBNA-1 antibody levels on MS risk, expressed on the OR scale, was 2.8 (95% CI 2.5-3.1), and the direct effect of IM history on MS risk was 1.7 (95% CI 1.5-2.0). A significant interaction between the two aspects of EBV infection was observed (RERI 1.2, 95% CI 0.3-2.0), accounting for about 50% of the total effect. Further, both aspects of EBV infection interacted with DRB1*15:01 and absence of A*02:01. Interpretation: Elevated anti-EBNA-1 antibody levels and IM history are different risk factors for MS. The two aspects of EBV infection act synergistically to increase MS risk, indicating that they partly are involved in the same biological pathways.


Solid-State Solvation and Enhanced Exciton Diffusion in Doped Organic Thin Films under Mechanical Pressure.
Direct modification of exciton energy has been previously used to optimize the operation of organic optoelectronic devices. One demonstrated method for exciton energy modification is through the use of the solvent dielectric effects in doped molecular films. To gain a deeper appreciation of the underlying physical mechanisms, in this work we test the solid-state solvation effect in molecular thin films under applied external pressure. We observe that external mechanical pressure increases dipole-dipole interactions, leading to shifts in the Frenkel exciton energy and enhancement of the time-resolved spectral red shift associated with the energy-transfer-mediated exciton diffusion. Measurements are performed on host:dopant molecular thin films, which show bathochromic shifts in photoluminescence (PL) under increasing pressure. This is in agreement with a simple solvation theory model of exciton energetics with a fitting parameter based on the mechanical properties of the host matrix material. We measure no significant change in exciton lifetime with increasing pressure, consistent with unchanged aggregation in molecular films under compression. However, we do observe an increase in exciton spectral thermalization rate for compressed molecular films, indicating enhanced exciton diffusion for increased dipole-dipole interactions under pressure. The results highlight the contrast between molecular energy landscapes obtained when dipole-dipole interactions are increased by the pressure technique versus the conventional dopant concentration variation methods, which can lead to extraneous effects such as aggregation at higher doping concentrations. The present work demonstrates the use of pressure-probing techniques in studying energy disorder and exciton dynamics in amorphous molecular thin films.


Patients' perceptions of research biopsies in phase I oncology trials.
Research biopsies are increasingly incorporated into phase I oncology trials resulting in ethical and logistical challenges for patients and clinicians. Patients' understanding and willingness to undergo these biopsies are crucial. Over 12 months, we administered a questionnaire comprising three sections: demographics and previous cancer therapy, understanding of phase I trials and personalized medicine, and understanding of biopsies and associated risks. Out of 56 patients approached, 47 patients completed the questionnaire. Overall, the patients were well informed about the concepts of personalized medicine and 89% (n = 42) were aware that early phase clinical trials aim to define a dose and explore side effects of new drugs. Interestingly, 76% (n = 36) expected early phase trials to improve symptoms, quality of life and survival. Offering hope and feeling in control of their treatment were important components for 80% (n = 38) and 57% (n = 27), respectively. The majority of this highly selective patient cohort understood the concept of research biopsies, with 59% (n = 28) willing to have a fresh research biopsy for trial participation. Although 72% (n = 34) felt that research biopsies should be optional, only 19% (n = 9) would not participate in a clinical trial with mandatory biopsies. Compared to diagnostic biopsies, the patients were less likely to accept associated risks with research biopsies. As research biopsies are crucial to many components of the drug development process, our study provides evidence for patients' overall willingness to undergo research biopsies for trial purposes. A consent process tailored to the biopsy site may help patients weigh up the associated risks versus benefits.


Disease Biomarker Query from RNA-Seq Data.
As a revolutionary way to unveil transcription, RNA-Seq technologies are challenging bioinformatics for its large data volumes and complexities. A large number of computational models have been proposed for differential expression (DE) analysis and normalization from different standing points. However, there were no studies available yet to conduct disease biomarker discovery for this type of high-resolution digital gene expression data, which will actually be essential to explore its potential in clinical bioinformatics. Although there were many biomarker discovery algorithms available in traditional omics communities, they cannot be applied to RNA-Seq count data to seek biomarkers directly for its special characteristics. In this work, we have presented a biomarker discovery algorithm, SEQ-Marker for RNA-Seq data, which is built on a novel data-driven feature selection algorithm, nonnegative singular value approximation (NSVA), which contributes to the robustness and sensitivity of the following DE analysis by taking advantages of the built-in characteristics of RNA-Seq count data. As a biomarker discovery algorithm built on network marker topology, the proposed SEQ-Marker not only bridges transcriptomics and systems biology but also contributes to clinical diagnostics.


The lack of paid sick leave as a barrier to cancer screening and medical care-seeking: results from the National Health Interview Survey.
Preventive health care services, such as cancer screening can be particularly vulnerable to a lack of paid leave from work since care is not being sought for illness or symptoms. We first describe the prevalence of paid sick leave by broad occupational categories and then examine the association between access to paid sick leave and cancer testing and medical care-seeking in the U.S. workforce. Data from the 2008 National Health Interview survey were analyzed by using paid sick leave status and other health-related factors to describe the proportion of U.S. workers undergoing mammography, Pap testing, endoscopy, fecal occult blood test (FOBT), and medical-care seeking. More than 48 million individuals (38%) in an estimated U.S. working population of 127 million did not have paid sick leave in 2008. The percentage of workers who underwent mammography, Pap test, endoscopy at recommended intervals, had seen a doctor during the previous 12 months or had at least one visit to a health care provider during the previous 12 months was significantly higher among those with paid sick leave compared with those without sick leave after controlling for sociodemographic and health-care-related factors. Lack of paid sick leave appears to be a potential barrier to obtaining preventive medical care and is a societal benefit that is potentially amenable to change.


Blood pressure risk factors in early adolescents: results from a Ugandan birth cohort.
We aimed to investigate life-course factors associated with blood pressure (BP) among Ugandan adolescents. Between 9th April 2003 and 24th November 2005, 2507 pregnant women from Entebbe municipality and Katabi sub-county were enrolled into a deworming trial. The resulting 2345 live-born offspring were followed to age 10 or 11 years, when between 20th May 2014 to 16th June 2016, BP was measured following standard protocols. Factors associated with BP were assessed using multivariable linear regression. BP was measured in 1119 adolescents with a median age of 10.2 years. Mean systolic BP and diastolic BP was 105.9 mmHg (standard deviation (SD) 8.2) and 65.2 mmHg (SD 7.3), respectively. Maternal gestational body mass index (BMI), higher maternal education status and family history of hypertension were positively associated with adolescent BP. Childhood (age ≤5 years) malaria was associated with lower adolescent systolic BP. Factors measured at time of BP measurement positively associated with systolic BP were age, BMI, waist circumference and Trichuris trichiura (whipworm) infection; higher vegetable consumption was associated with lower systolic BP. Results for diastolic BP were similar, except higher fruit, rather than higher vegetable consumption was associated with lower diastolic BP and there was no association with waist circumference or Trichuris trichiura infection. In summary, life-course exposures were associated with adolescent BP in this tropical birth cohort. Malaria early in life could impact later BP. Interventions initiated early in life targeting individuals with family history of hypertension, aiming to reduce adiposity (in pregnancy and adolescence) and promoting fruit and vegetable consumption might contribute to reducing the risk of high BP and subsequent cardiovascular diseases.


Flow-through cross-polarized imaging as a new tool to overcome the analytical sensitivity challenges of a low-dose crystalline compound in a lipid matrix.
Assessing the physical state of a low-dose active compound in a solid lipid or polymer matrix is analytically challenging, especially if the matrix exhibits some crystallinity. The aim of this study was first to compare the ability of current methods to detect the presence of a crystalline model compound in lipid matrices. Subsequently, a new technique was introduced and evaluated because of sensitivity issues that were encountered with current methods. The new technique is a flow-through version of cross-polarized imaging in transmission mode. The tested lipid-based solid dispersions (SDs) consisted of β-carotene (BC) as a model compound, and of Gelucire 50/13 or Geleol mono- and diglycerides as lipid matrices. The solid dispersions were analyzed by (hyper) differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), and microscopic techniques including atomic force microscopy (AFM). DSC and XRPD could analyze crystalline BC at concentrations as low as 3% (w/w) in the formulations. However, with microscopic techniques crystalline particles were detected at significantly lower concentrations of even 0.5% (w/w) BC. A flow-through cross-polarized imaging technique was introduced that combines the advantage of analyzing a larger sample size with high sensitivity of microscopy. Crystals were detected easily in samples containing even less than 0.2% (w/w) BC. Moreover, the new tool enabled approximation of the kinetic BC solubility in the crystalline lipid matrices. As a conclusion, the flow-through cross-polarized imaging technique has the potential to become an indispensable tool for characterizing low-dose crystalline compounds in a lipid or polymer matrix of solid dispersions.


Bacterial infections in Myd88-deficient mice.
Three breeding colonies of Myd88(-/-) mice had a history of significant morbidity and mortality. Although strain-specific poor reproductive performance might explain neonatal death and dystocia, mice were found dead or required euthanasia because of moribundity, distended abdomen, head tilt, and seizures. Histopathology results included bacteremia, placentitis, metritis, peritonitis with abscess formation, and suppurative meningoencephalitis. Intralesional gram-negative coccobacilli were present, often in extremely high number. Cultures of samples of the cardiac blood of a mouse and from water-bottle sipper tubes provided to some affected mice grew Pseudomonas aeruginosa. In addition, affected tissues from 2 mice and feces from a third tested PCR-positive for P. aeruginosa. Although the mice had received autoclaved reverse-osmosis-purified drinking water, we suspect that the mice were inoculated with P. aeruginosa through contaminated sipper tubes. Because of the deficiency in most of the Toll-like receptor signaling pathways, these Myd88(-/-) mice were unlikely to have developed competitive innate and adaptive immune responses, resulting in bacterial infections. These clinical cases underscore the importance of understanding how genotype, phenotype and environment affect animal health. Sound husbandry and experimental practices are needed to prevent the exposure of immuno-deficient mice to pathogens.


A simplified laminin nomenclature.
A simplification of the laminin nomenclature is presented. Laminins are multidomain heterotrimers composed of alpha, beta and gamma chains. Previously, laminin trimers were numbered with Arabic numerals in the order discovered, that is laminins-1 to -5. We introduce a new identification system for a trimer using three Arabic numerals, based on the alpha, beta and gamma chain numbers. For example, the laminin with the chain composition alpha5beta1gamma1 is termed laminin-511, and not laminin-10. The current practice is also to mix two overlapping domain and module nomenclatures. Instead of the older Roman numeral nomenclature and mixed nomenclature, all modules are now called domains. Some domains are renamed or renumbered. Laminin epidermal growth factor-like (LE) domains are renumbered starting at the N-termini, to be consistent with general protein nomenclature. Domain IVb of alpha chains is named laminin 4a (L4a), domain IVa of alpha chains is named L4b, domain IV of gamma chains is named L4, and domain IV of beta chains is named laminin four (LF). The two coiled-coil domains I and II are now considered one laminin coiled-coil domain (LCC). The interruption in the coiled-coil of beta chains is named laminin beta-knob (Lbeta) domain. The chain origin of a domain is specified by the chain nomenclature, such as alpha1L4a. The abbreviation LM is suggested for laminin. Otherwise, the nomenclature remains unaltered.


Protein arginine methyltransferase 5 regulates ERK1/2 signal transduction amplitude and cell fate through CRAF.
The RAS to extracellular signal-regulated kinase (ERK) signal transduction cascade is crucial to cell proliferation, differentiation, and survival. Although numerous growth factors activate the RAS-ERK pathway, they can have different effects on the amplitude and duration of the ERK signal and, therefore, on the biological consequences. For instance, nerve growth factor, which elicits a larger and more sustained increase in ERK phosphorylation in PC12 cells than does epidermal growth factor (EGF), stimulates PC12 cell differentiation, whereas EGF stimulates PC12 cell proliferation. Here, we show that protein arginine methylation limits the ERK1/2 signal elicited by particular growth factors in different cell types from various species. We found that this restriction in ERK1/2 phosphorylation depended on methylation of RAF proteins by protein arginine methyltransferase 5 (PRMT5). PRMT5-dependent methylation enhanced the degradation of activated CRAF and BRAF, thereby reducing their catalytic activity. Inhibition of PRMT5 activity or expression of RAF mutants that could not be methylated not only affected the amplitude and duration of ERK phosphorylation in response to growth factors but also redirected the response of PC12 cells to EGF from proliferation to differentiation. This additional level of regulation within the RAS pathway may lead to the identification of new targets for therapeutic intervention.


Nonelective surgery at night and in-hospital mortality: Prospective observational data from the European Surgical Outcomes Study.
Evidence suggests that sleep deprivation associated with night-time working may adversely affect performance resulting in a reduction in the safety of surgery and anaesthesia. Our primary objective was to evaluate an association between nonelective night-time surgery and in-hospital mortality. We hypothesised that urgent surgery performed during the night was associated with higher in-hospital mortality and also an increase in the duration of hospital stay and the number of admissions to critical care. A prospective cohort study. This is a secondary analysis of a large database related to perioperative care and outcome (European Surgical Outcome Study). Four hundred and ninety-eight hospitals in 28 European countries. Men and women older than 16 years who underwent nonelective, noncardiac surgery were included according to time of the procedure. None. Primary outcome was in-hospital mortality; the secondary outcome was the duration of hospital stay and critical care admission. Eleven thousand two hundred and ninety patients undergoing urgent surgery were included in the analysis with 636 in-hospital deaths (5.6%). Crude mortality odds ratios (ORs) increased sequentially from daytime [426 deaths (5.3%)] to evening [150 deaths (6.0%), OR 1.14; 95% confidence interval 0.94 to 1.38] to night-time [60 deaths (8.3%), OR 1.62; 95% confidence interval 1.22 to 2.14]. Following adjustment for confounding factors, surgery during the evening (OR 1.09; 95% confidence interval 0.91 to 1.31) and night (OR 1.20; 95% confidence interval 0.9 to 1.6) was not associated with an increased risk of postoperative death. Admittance rate to an ICU increased sequentially from daytime [891 (11.1%)], to evening [347 (13.8%)] to night time [149 (20.6%)]. In patients undergoing nonelective urgent noncardiac surgery, in-hospital mortality was associated with well known risk factors related to patients and surgery, but we did not identify any relationship with the time of day at which the procedure was performed. Clinicaltrials.gov identifier: NCT01203605.


Beyond the sticker price: including and excluding time in comparing food prices.
An ongoing debate in the literature is how to measure the price of food. Most analyses have not considered the value of time in measuring the price of food. Whether or not the value of time is included in measuring the price of a food may have important implications for classifying foods based on their relative cost. The purpose of this article is to compare prices that exclude time (time-exclusive price) with prices that include time (time-inclusive price) for 2 types of home foods: home foods using basic ingredients (home recipes) vs. home foods using more processed ingredients (processed recipes). The time-inclusive and time-exclusive prices are compared to determine whether the time-exclusive prices in isolation may mislead in drawing inferences regarding the relative prices of foods. We calculated the time-exclusive price and time-inclusive price of 100 home recipes and 143 processed recipes and then categorized them into 5 standard food groups: grains, proteins, vegetables, fruit, and dairy. We then examined the relation between the time-exclusive prices and the time-inclusive prices and dietary recommendations. For any food group, the processed food time-inclusive price was always less than the home recipe time-inclusive price, even if the processed food's time-exclusive price was more expensive. Time-inclusive prices for home recipes were especially higher for the more time-intensive food groups, such as grains, vegetables, and fruit, which are generally underconsumed relative to the guidelines. Focusing only on the sticker price of a food and ignoring the time cost may lead to different conclusions about relative prices and policy recommendations than when the time cost is included.


Human lipoprotein lipase complementary DNA sequence.
Lipoprotein lipase is a key enzyme of lipid metabolism that acts to hydrolyze triglycerides, providing free fatty acids for cells and affecting the maturation of circulating lipoproteins. It has been proposed that the enzyme plays a role in the development of obesity and atherosclerosis. The human enzyme has been difficult to purify and its protein sequence was heretofore undetermined. A complementary DNA for human lipoprotein lipase that codes for a mature protein of 448 amino acids has now been cloned and sequenced. Analysis of the sequence indicates that human lipoprotein lipase, hepatic lipase, and pancreatic lipase are members of a gene family. Two distinct species of lipoprotein lipase messenger RNA that arise from alternative sites of 3'-terminal polyadenylation were detected in several different tissues.


An exploratory study of stress and coping among Black college men.
Research on coping mechanisms among Black Americans is robust, yet there is a dearth of studies that use qualitative approaches to examine coping specifically among young Black men. The current and historical landscape of race relations in the United States calls for additional concern and exploration of this topic. To fill gaps in this area, this study uncovered the ways Black college men cope with various stressors that impact their mental health. Eleven qualitative interviews were conducted with 18- to 25-year-old Black men enrolled at a college in the Midwest who participated in the Young Black Men, Masculinities, and Mental Health (YBMen) project. Data were analyzed using a rigorous and accelerated data reduction technique that involved transferring transcript data onto spreadsheets, reducing the data, and conducting a rigorous content analysis to generate themes and subthemes. Participants reported that Black college men cope with stress by discussing their issues with members of their social support networks, engaging in physical activities, and relying on themselves. Some respondents reported that they intentionally avoided dealing with their mental health, whereas others attempted to make sense of their problems. Substance use, violence, and anger were all identified as markers of unaddressed stressors. Stigma emerged as a barrier to seeking help. Study findings highlight within-group differences among Black college men. Mental health researchers must continue to develop creative ways to examine stress and coping so that resources can become more culturally relevant and readily available both within and outside of the spaces Black men occupy. (PsycINFO Database Record


Cellular effects of cannabinoids.
The many studies that have been included in this review suggest that cannabinoids have ubiquitous effects on biological systems. These results also underscore the intensity to which cannabinoids have been studied. While there are numerous reasons for the prodigious amount of cannabinoid research, a major stimulus has been the desire to identify a specific biochemical event or pathway that is responsible for the expression of delta 9-THC's unique psychoactivity. It is the hope that delta 9-THC, as with all centrally acting drugs, might serve as an important tool for achieving a better understanding of the central nervous system. As discussed in this review, the psychoactivity of cannabinoids might best be described as a composite of numerous effects. If that is indeed the case, then it would seem logical that these centrally mediated effects do not arise from a single biochemical alteration, but rather from multiple actions. Of course, a major problem arises when one attempts to establish a relationship between cause and effect when multiple mechanisms and effects are involved. An initial approach to reducing the complexity of elucidation of mechanism of action should involve attempts to distinguish those cannabinoid actions which result in specific effects (psychoactivity) from those which produce non-psychoactive effects (such as general depression). There are several fundamental principles that can be used to assess specificity, including concentration or dose of the drug that is required to produce a given effect. Low doses of delta 9-THC are capable of producing the psychoactivity that is unique to cannabinoids, whereas higher doses may produce effects that are both specific and nonspecific for cannabinoids. Unfortunately, establishing this basic tenet for delta 9-THC has proven to be difficult. It has not been possible to establish the concentration of delta 9-THC at its site of action that is necessary to produce a given pharmacological effect. While it is a simple matter to measure the concentration of cannabinoids in either a whole tissue or an incubation medium, the hydrophobicity of cannabinoids dramatically affects their affinity for, and hence concentration in, the biochemical components of the tissue. If the concentration of delta 9-THC could be measured at its site of action, then the relevance of many of its pharmacological effects could be adequately determined. Two possible mechanisms by which cannabinoids might produce psychoactivity are membrane perturbation and receptor interactions, and indeed, both mechanisms have received considerable attention.(ABSTRACT TRUNCATED AT 400 WORDS)


Correlation between hand/wrist and panoramic radiographs in severe secondary hyperparathyroidism.
Hand/wrist and dental radiographs are important for osteoporosis analysis in secondary hyperparathyroidism (SHPT). This study evaluated whether a correlation exists between the effects of the disease on the hands and jaws, and investigated the association between osteoporosis progression in the hands and parathyroid hormone (PTH) levels in chronic kidney disease (CKD) patients. Four panoramic radiographic parameters (mental index, mandibular cortical index, trabecular bone pattern, and calcification/resorption) and four corresponding hand/wrist radiographic parameters (metacarpal cortical thickness, phalangeal cortical index, trabecular bone pattern, and calcification/resorption) were applied to investigate possible correlation between the effects of SHPT on the jaws and hands/wrists, by Spearman's correlation coefficient. PTH levels and the hand/wrist radiographic parameters were also tested by spearman's correlation coefficient (p < 0.05). The presence of brown tumors, vascular calcifications, and acroosteolysis on the hands was also evaluated. Mandibular cortical index was strongly correlated with the phalangeal cortical index (p = 0.000). Phalangeal cortical index and trabecular bone pattern of hand/wrist correlated with PTH levels (0.002 and 0.000, respectively). Brown tumors occurred in four CKD patients, while both vascular calcifications and acroosteolysis were observed in 19 patients. There is a significant correlation between the morphological changes caused by secondary hyperparathyroidism in hand and jaw bones. The morphological status can be assessed using the mandibular cortical index, besides the phalangeal cortical index. The latter correlates well with parathyroid hormone levels of advanced chronic kidney disease. Panoramic images reveal morphological changes in the jaw bone, indicating likewise changes in the hand/wrist in severe secondary hyperparathyroidism. The severity of the bone changes may be a reflection of the parathyroid hormone levels in advanced chronic kidney disease.


A systems biology approach to the hepatic role of the oxysterol receptor LXR in the regulation of lipogenesis highlights a cross-talk with PPARα.
The Liver X Receptors (LXRs) α and β and the Peroxisome Proliferator-Activated Receptor α (PPARα) are transcription factors that belong to class II nuclear receptors. They drive the expression of genes involved in hepatic lipid homeostasis and therefore are important targets for the prevention and treatment of nonalcoholic fatty liver disease (NAFLD). LXRs and PPARα are regulated by endogenous ligands, oxysterols and fatty acid derived molecules, respectively. In the liver, pharmacological activation of LXRs leads to the over-expression of genes involved in de novo lipogenesis, while PPARα is critical for fatty acid catabolism in nutrient deprivation. Even if these two nuclear receptors seemed to play opposite parts, recent studies have highlighted that PPARα also influence the expression of genes involved in fatty acids synthesis. In this study, we used pharmacological approaches and genetically engineered mice to investigate the cross-talk between LXRs and PPARα in the regulation of genes responsible for lipogenesis. We first investigated the effect of T0901317 and fenofibrate, two synthetic agonists of LXRs and PPARα, respectively. As expected, T0901317 and fenofibrate induce expression of genes involved LXR-dependent and PPARα-dependent lipogenic responses. Considering such overlapping effect, we then tested whether LXR agonist may influence PPARα driven response and vice versa. We show that the lack of PPARα does not influence the effects of T0901317 on lipogenic genes expression. However, PPARα deficiency prevents the up-regulation of genes involved in ω-hydroxylation that are induced by the LXR agonist. In addition, over-expression of lipogenic genes in response to fenofibrate is decreased in LXR knockout mice as well as the expression of PPARα target genes involved in fatty acid oxidation. Altogether, our work provides in vivo evidence for a central interconnection between nuclear receptors that drive hepatic lipid metabolism in response to oxysterol and fatty acids.


Personality predicts social dominance in male domestic fowl.
Individuals in social species commonly form dominance relationships, where dominant individuals enjoy greater access to resources compared to subordinates. A range of factors such as sex, age, body size and prior experiences has to varying degrees been observed to affect the social status an individual obtains. Recent work on animal personality (i.e. consistent variation in behavioural responses of individuals) demonstrates that personality can co-vary with social status, suggesting that also behavioural variation can play an important role in establishment of status. We investigated whether personality could predict the outcome of duels between pairs of morphologically matched male domestic fowl (Gallus gallus domesticus), a species where individuals readily form social hierarchies. We found that males that more quickly explored a novel arena, or remained vigilant for a longer period following the playback of a warning call were more likely to obtain a dominant position. These traits were uncorrelated to each other and were also uncorrelated to aggression during the initial part of the dominance-determining duel. Our results indicate that several behavioural traits independently play a role in the establishment of social status, which in turn can have implications for the reproductive success of different personality types.


Tunneling spectroscopy measurements on hydrogen-bonded supramolecular polymers.
We studied the formation of hydrogen-bonded supramolecular polymers of Ethyl Hexyl Urea Toluene (EHUT) on a gold (111) surface by low temperature scanning tunneling microscopy. Tunneling spectroscopy performed along an individual molecule embedded in a self-assembled layer revealed strong changes in the value of the HOMO-LUMO gap. A variation of the LUMO state is attributed to the effect of space charge accumulation resulting from anisotropic adhesion of the molecule. In addition, for specific tunneling conditions, changes induced through the formation of hydrogen bonds became visible in the differential conductance (dI/dV) maps; isolated molecules, hydrogen bonded dimers and supramolecular polymers of EHUT were distinguishable through their electronic properties.


The alternative workplace: changing where and how people work.
Today many organizations, including AT&T and IBM, are pioneering the alternative workplace--the combination of nontraditional work practices, settings, and locations that is beginning to supplement traditional offices. This is not a fad. Although estimates vary widely, it is safe to say that some 30 million to 40 million people in the United States are now either telecommuters or home-based workers. What motivates managers to examine how people spend their time at the office and where else they might do their work? Among the potential benefits for companies are reduced costs, increased productivity, and an edge in vying for and keeping talented employees. They can also capture government incentives and avoid costly sanctions. But at the same time, alternative workplace programs are not for everyone. Indeed, such programs can be difficult to adopt, even for those organizations that seem to be most suited to them. Ingrained behaviors and practical hurdles are hard to overcome. And the challenges of managing both the cultural changes and systems improvements required by an alternative workplace initiative are substantial. How should senior managers think about alternative workplace programs? What are the criteria for determining whether the alternative workplace is right for a given organization? What are the most common pitfalls in implementing alternative workplace programs? The author provides the answers to these questions in his examination of this new frontier of where and how people work.


Rational incorporation of selenium into temozolomide elicits superior antitumor activity associated with both apoptotic and autophagic cell death.
The DNA alkylating agent temozolomide (TMZ) is widely used in the treatment of human malignancies such as glioma and melanoma. On the basis of previous structure-activity studies, we recently synthesized a new TMZ selenium analog by rationally introducing an N-ethylselenocyanate extension to the amide functionality in TMZ structure. This TMZ-Se analog showed a superior cytotoxicity to TMZ in human glioma and melanoma cells and a more potent tumor-inhibiting activity than TMZ in mouse glioma and melanoma xenograft model. TMZ-Se was also effective against a TMZ-resistant glioma cell line. To explore the mechanism underlying the superior antitumor activity of TMZ-Se, we compared the effects of TMZ and TMZ-Se on apoptosis and autophagy. Apoptosis was significantly increased in tumor cells treated with TMZ-Se in comparison to those treated with TMZ. TMZ-Se also triggered greater autophagic response, as compared with TMZ, and suppressing autophagy partly rescued cell death induced by TMZ-Se, indicating that TMZ-Se-triggered autophagy contributed to cell death. Although mRNA level of the key autophagy gene, Beclin 1, was increased, Beclin 1 protein was down-regulated in the cells treated with TMZ-Se. The decrease in Beclin 1 following TMZ-Se treatment were rescued by the calpain inhibitors and the calpain-mediated degradation of Beclin1 had no effect on autophagy but promoted apoptosis in cells treated with TMZ-Se. Our study indicates that incorporation of Se into TMZ can render greater potency to this chemotherapeutic drug.


Synaptotagmin-1 and Doc2b Exhibit Distinct Membrane-Remodeling Mechanisms.
Synaptotagmin-1 (Syt1) is a calcium sensor protein that is critical for neurotransmission and is therefore extensively studied. Here, we use pairs of optically trapped beads coated with SNARE-free synthetic membranes to investigate Syt1-induced membrane remodeling. This activity is compared with that of Doc2b, which contains a conserved C2AB domain and induces membrane tethering and hemifusion in this cell-free model. We find that the soluble C2AB domain of Syt1 strongly affects the probability and strength of membrane-membrane interactions in a strictly Ca2+- and protein-dependent manner. Single-membrane loading of Syt1 yielded the highest probability and force of membrane interactions, whereas in contrast, Doc2b was more effective after loading both membranes. A lipid-mixing assay with confocal imaging reveals that both Syt1 and Doc2b are able to induce hemifusion; however, significantly higher Syt1 concentrations are required. Consistently, both C2AB fragments cause a reduction in the membrane-bending modulus, as measured by a method based on atomic force microscopy. This lowering of the energy required for membrane deformation may contribute to Ca2+-induced fusion.