Voltammetric studies of the reactions of iron-sulphur clusters ([3Fe-4S] or [M3Fe-4S]) formed in Pyrococcus furiosus ferredoxin.
Reactions of the [3Fe-4S] cluster and various metallated [M3Fe-4S] adducts co-ordinated in the ferredoxin from the hyperthermophile Pyrococcus furiosus have been studied by protein-film voltammetry, bulk-solution voltammetry, solution kinetics and magnetic CD (MCD). The [3Fe-4S] cluster exhibits two couples, [3Fe-4S]+/0 and [3Fe-4S]0/2-. Film voltammetry is possible over a wide pH range (2-8), revealing that the [3Fe-4S]+/0 couple shows a complex pH dependence with pKred1=2.8, pKox=4.9 and pKred2=6.7. From MCD, pKred1 corresponds with protonation of [3Fe-4S]0 to give a spectroscopically distinct species, as reported for ferredoxins from Azotobacter and Sulfolobus. The status of the disulphide/disulphydryl entity makes no significant difference to the data (given for the -S-S- form). Formation of the hyper-reduced [3Fe-4S]2- state is observed, requiring 3H+ for the overall 3e- reduction of [3Fe-4S]+, the change therefore being electroneutral. By comparison with the ferredoxin from Desulfovibrio africanus, uptake of Fe(II) and other M(II) by [3Fe-4S]0 to give [M3Fe-4S] clusters is slow (t1/2>10 min at room temperature, slower still if the protein is adsorbed on the electrode), whereas reaction with Tl(I) to produce [Tl3Fe-4S] is very rapid (t1/2<<1 s), suggesting that co-ordination of Tl does not require reorganization of the protein structure. Rates of formation of [3Fe-4S] from [M3Fe-4S] adducts increase sharply at high potentials, showing that metal release involves a labile 'super-oxidized' [M3Fe-4S]3+ state.


A systematic genetic screen for genes involved in sensing inorganic phosphate availability in Saccharomyces cerevisiae.
Saccharomyces cerevisiae responds to changes in extracellular inorganic phosphate (Pi) availability by regulating the activity of the phosphate-responsive (PHO) signaling pathway, enabling cells to maintain intracellular levels of the essential nutrient Pi. Pi-limitation induces upregulation of inositol heptakisphosphate (IP7) synthesized by the inositol hexakisphosphate kinase Vip1, triggering inhibition of the Pho80/Pho85 cyclin-cyclin dependent kinase (CDK) complex by the CDK inhibitor Pho81, which upregulates the PHO regulon through the CDK target and transcription factor Pho4. To identify genes that are involved in signaling upstream of the Pho80/Pho85/Pho81 complex and how they interact with each other to regulate the PHO pathway, we performed genome-wide screens with the synthetic genetic array method. We identified more than 300 mutants with defects in signaling upstream of the Pho80/Pho85/Pho81 complex, including AAH1, which encodes an adenine deaminase that negatively regulates the PHO pathway in a Vip1-dependent manner. Furthermore, we showed that even in the absence of VIP1, the PHO pathway can be activated under prolonged periods of Pi starvation, suggesting complexity in the mechanisms by which the PHO pathway is regulated.


Age-associated alteration of gene expression patterns in mouse oocytes.
Decreasing oocyte competence with maternal aging is a major factor in human infertility. To investigate the age-dependent molecular changes in a mouse model, we compared the expression profiles of metaphase II oocytes collected from 5- to 6-week-old mice with those collected from 42- to 45-week-old mice using the NIA 22K 60-mer oligo microarray. Among approximately 11,000 genes whose transcripts were detected in oocytes, about 5% (530) showed statistically significant expression changes, excluding the possibility of global decline in transcript abundance. Consistent with the generally accepted view of aging, the differentially expressed genes included ones involved in mitochondrial function and oxidative stress. However, the expression of other genes involved in chromatin structure, DNA methylation, genome stability and RNA helicases was also altered, suggesting the existence of additional mechanisms for aging. Among the transcripts decreased with aging, we identified and characterized a group of new oocyte-specific genes, members of the human NACHT, leucine-rich repeat and PYD-containing (NALP) gene family. These results have implications for aging research as well as for clinical ooplasmic donation to rejuvenate aging oocytes.


nhl-2 Modulates microRNA activity in Caenorhabditis elegans.
TRIM-NHL proteins represent a large class of metazoan proteins implicated in development and disease. We demonstrate that a C. elegans TRIM-NHL protein, NHL-2, functions as a cofactor for the microRNA-induced silencing complex (miRISC) and thereby enhances the posttranscriptional repression of several genetically verified microRNA targets, including hbl-1 and let-60/Ras (by the let-7 family of microRNAs) and cog-1 (by the lsy-6 microRNA). NHL-2 is localized to cytoplasmic P-bodies and physically associates with the P-body protein CGH-1 and the core miRISC components ALG-1/2 and AIN-1. nhl-2 and cgh-1 mutations compromise the repression of microRNA targets in vivo but do not affect microRNA biogenesis, indicating a role for an NHL-2:CGH-1 complex in the effector phase of miRISC activity. We propose that the NHL-2:CGH-1 complex functions in association with mature miRISC to modulate the efficacy of microRNA:target interactions in response to physiological and developmental signals, thereby ensuring the robustness of genetic regulatory pathways regulated by microRNAs.


Quantitative rt-PCR analysis of uncoupling protein isoforms in mouse brain cortex: methodological optimization and comparison of expression with brown adipose tissue and skeletal muscle.
Uncoupling proteins (UCPs) present in the inner mitochondrial membrane are involved in uncoupling respiration from ATP synthesis. Five UCP isoforms have been identified but information about their presence and level of expression in the central nervous system remains incomplete. To determine the nature and proportion of UCP isoform mRNAs present in brain cortex, we developed and optimized a specific quantitative reverse-transcription polymerase chain reaction procedure. Optimal range of RNA concentrations to be used in the reverse-transcriptase reaction was determined. Primer design and concentration were optimized for each target gene while polymerase chain reaction efficiency was assessed for a range of reverse-transcriptase dilutions. Genomic contribution to the quantitative signal was evaluated for each isoform and minimized. Three reference genes were tested for normalization, and beta-actin was found to be the most stable among tissues. Results indicate that brain cortex contains significant amounts of all UCP mRNAs, with UCP5 and UCP4 being the most abundant, as opposed to brown adipose tissue and skeletal muscle, which predominantly express UCP1 and UCP3, respectively. These data provide a first quantitative assessment of UCP mRNA expression in mouse brain, showing the presence of all five isoforms with distinct proportions, thus suggesting specific roles in the central nervous system.


A self-calibrating method for photogeometric acquisition of 3D objects.
We present a self-calibrating photogeometric method using only off--the-shelf hardware that enables quickly and robustly obtaining multimillion point-sampled and colored models of real-world objects. Some previous efforts use a priori calibrated systems to separately acquire geometric and photometric information. Our key enabling observation is that a digital projector can be simultaneously used as either an active light source or as a virtual camera (as opposed to a digital camera, which cannot be used for both). We present our self--calibrating and multiviewpoint 3D acquisition method, based on structured light, which simultaneously obtains mutually registered surface position and surface normal information and produces a single high-quality model. Acquisition processing freely alternates between using a geometric setup and using a photometric setup with the same hardware configuration. Further, our approach generates reconstructions at the resolution of the camera and not only the projector. We show the results of capturing several high-quality models of real--world objects.


Remotely Sensed Environmental Conditions and Malaria Mortality in Three Malaria Endemic Regions in Western Kenya.
Malaria is an important cause of morbidity and mortality in malaria endemic countries. The malaria mosquito vectors depend on environmental conditions, such as temperature and rainfall, for reproduction and survival. To investigate the potential for weather driven early warning systems to prevent disease occurrence, the disease relationship to weather conditions need to be carefully investigated. Where meteorological observations are scarce, satellite derived products provide new opportunities to study the disease patterns depending on remotely sensed variables. In this study, we explored the lagged association of Normalized Difference Vegetation Index (NVDI), day Land Surface Temperature (LST) and precipitation on malaria mortality in three areas in Western Kenya. The lagged effect of each environmental variable on weekly malaria mortality was modeled using a Distributed Lag Non Linear Modeling approach. For each variable we constructed a natural spline basis with 3 degrees of freedom for both the lag dimension and the variable. Lag periods up to 12 weeks were considered. The effect of day LST varied between the areas with longer lags. In all the three areas, malaria mortality was associated with precipitation. The risk increased with increasing weekly total precipitation above 20 mm and peaking at 80 mm. The NDVI threshold for increased mortality risk was between 0.3 and 0.4 at shorter lags. This study identified lag patterns and association of remote- sensing environmental factors and malaria mortality in three malaria endemic regions in Western Kenya. Our results show that rainfall has the most consistent predictive pattern to malaria transmission in the endemic study area. Results highlight a potential for development of locally based early warning forecasts that could potentially reduce the disease burden by enabling timely control actions.


Consensus clustering approach to group brain connectivity matrices.
A novel approach rooted on the notion of consensus clustering, a strategy developed for community detection in complex networks, is proposed to cope with the heterogeneity that characterizes connectivity matrices in health and disease. The method can be summarized as follows: (a) define, for each node, a distance matrix for the set of subjects by comparing the connectivity pattern of that node in all pairs of subjects; (b) cluster the distance matrix for each node; (c) build the consensus network from the corresponding partitions; and (d) extract groups of subjects by finding the communities of the consensus network thus obtained. Different from the previous implementations of consensus clustering, we thus propose to use the consensus strategy to combine the information arising from the connectivity patterns of each node. The proposed approach may be seen either as an exploratory technique or as an unsupervised pretraining step to help the subsequent construction of a supervised classifier. Applications on a toy model and two real datasets show the effectiveness of the proposed methodology, which represents heterogeneity of a set of subjects in terms of a weighted network, the consensus matrix.


Avoiding Resistance Limitations in High-Performance Transparent Supercapacitor Electrodes Based on Large-Area, High-Conductivity PEDOT:PSS Films.
This work describes the potential of thin, spray-deposited, large-area poly(3,4-ethylenedioxythiophene)/poly(styrene-4-sulfonate) ( PSS) conducting polymer films for use as transparent supercapacitor electrodes. To facilitate this, we provide a detailed explanation of the factors limiting the performance of such electrodes. These films have a very low optical conductivity of σop = 24 S/cm (at 550 nm), crucial for this application, and a reasonable volumetric capacitance of CV = 41 F/cm(3). Secondary doping with formic acid gives these films a DC conductivity of σDC = 936 S/cm, allowing them to perform both as a transparent conductor/current collector and transparent supercapacitor electrode. Small-area films (A ∼ 1 cm(2)) display measured areal capacitance as high as 1 mF/cm(2), even for reasonably transparent electrodes (T ∼ 80%). However, in real devices, the absolute capacitance will be maximized by increasing the device area. As such, here, we measure the electrode performance as a function of its length and width. We find that the measured areal capacitance falls dramatically with scan rate and sample length but is independent of width. We show that this is because the measured areal capacitance is limited by the electrical resistance of the electrode. We have derived an equation for the measured areal capacitance as a function of scan rate and electrode lateral dimensions that fits the data extremely well up to scan rates of ∼1000 mV/s (corresponding to charge/discharge times > 0.6 s). These results are self-consistent with independent analysis of the electrical and impedance properties of the electrodes. These results can be used to find limiting combinations of electrode length and scan rate, beyond which electrode performance falls dramatically. We use these insights to build large-area (∼100 cm(2)) supercapacitors using electrodes that are 95% transparent, providing a capacitance of ∼12 mF (at 50 mV/s), significantly higher than that of any previously reported transparent supercapacitor.


Comparison of quartz-tungsten-halogen, light-emitting diode, and plasma arc curing lights.
This study determined which light source was best at photopolymerizing five representative brands of resin composite. The hypothesis was that there would be no difference in the hardness of the composites when irradiated by any of the lights. Six curing light/tip combinations were used to photopolymerize five resin composites. In accordance with the manufacturer's instructions, the PAC light was used for 3 s and the high intensity QTH light was used for 5 s. The other QTH and LED lights were used for 40 s. To represent the clinical environment, the samples were irradiated at a distance of 2 and 9 mm away from the tip of the light guide. The Knoop hardness was measured at the top and bottom of the composites after 15 min and again at 24 h. The hardness data were compared using a general linear model analysis with Sidak's adjustment for multiple comparisons with p < 0.01 as the level of significance. The 6 curing light/tip combinations had different effects on the hardness of the 5 composites (p < 0.01). The two LED lights could not cure the neutral shade of Pyramid Enamel in 40 s. As the distance increased from 2 to 9 mm, the decrease in hardness was not similar amongst the different light/tips and composite combinations (p < 0.0012). The curing light/tip combination which delivered the greatest total energy produced the hardest specimens. 1) The 6 curing light/tip combinations had different effects on the hardness of the 5 composites (p < 0.01). 2) Neither of the two LED lights used was able to adequately polymerize the five resin composites tested. 3) The QTH light, which delivered the greatest total energy, always produced the hardest resin composite. 4) When the distance of the composites from the light guides was increased, the effect on their hardness was not the same for all light/tip combinations. It is therefore not possible to predict the performance of a curing light at 9 mm based upon power density measurements or hardness data recorded when the tip of the light guide is 2 mm away.


Enrichment of amyloidogenesis at an air-water interface.
The aggregation of proteins or peptides into amyloid fibrils is a hallmark of protein misfolding diseases (e.g., Alzheimer's disease) and is under intense investigation. Many of the experiments performed are in vitro in nature and the samples under study are ordinarily exposed to diverse interfaces, e.g., the container wall and air. This naturally raises the question of how important interfacial effects are to amyloidogenesis. Indeed, it has already been recognized that many amyloid-forming peptides are surface-active. Moreover, it has recently been demonstrated that the presence of a hydrophobic interface can promote amyloid fibrillization, although the underlying mechanism is still unclear. Here, we combine theory, surface property measurements, and amyloid fibrillogenesis assays on islet amyloid polypeptide and amyloid-β peptide to demonstrate why, at experimentally relevant concentrations, the surface activity of the amyloid-forming peptides leads to enriched fibrillization at an air-water interface. Our findings indicate that the key that links these two seemingly different phenomena is the surface-active nature of the amyloid-forming species, which renders the surface concentration much higher than the corresponding critical fibrillar concentration. This subsequently leads to a substantial increase in fibrillization.


See One, Be One, Teach One: Faculty Use of Their Personal Health Narratives in Teaching.
Despite extensive examination of physician self-disclosure to patients and colleagues, no studies have directly investigated if physician faculty disclose personal health information to trainees for clinical teaching purposes. This study examines the types of personal medical information (personal health narratives) family medicine faculty use during resident teaching encounters and the beliefs of family medicine faculty about such disclosure. Due to the exploratory nature of this study, the authors relied upon the triangulation of qualitative research methods to verify the use of and purpose for sharing personal health narratives by family physician faculty during teaching encounters. Direct observation, depth interviews, an attitude survey, and focus groups were sequentially used to evoke their beliefs about the purpose, benefits, and risks of sharing personal health narratives with residents. Ninety-eight percent of survey respondents acknowledged using personal health narratives in teaching, and half reported doing so infrequently. A large majority considered the practice an effective teaching method, but respondents were divided on potential risks. Focus group participants believed that disclosing health information is a powerful teaching method that should be utilized purposefully. Participants identified a need for guidance on how to effectively incorporate personal health narratives during teaching. The use of personal health narratives in teaching is well accepted among the physician faculty in this study. Although participants endorsed the practice, none had been trained to integrate self-disclosure in teaching, and most had not consciously considered the limits and risks of sharing their health histories with residents. Further research is needed to determine the prevalence, range, and depth of faculty disclosure in teaching and to assess the impact on learners.


Accepters, fence sitters, or rejecters: Moral profiles of vaccination attitudes.
Childhood vaccination is a safe and effective way of reducing infectious diseases. Yet, public confidence in vaccination is waning, driven in part by the 'manufacture of doubt' by anti-vaccination activists and websites. However, there is little research examining the psychological underpinnings of anti-vaccination rhetoric among parents. Here, we examined the structure and moral roots of anti-vaccination attitudes amongst Australian parents active on social media parenting sites. Participants (N = 296) completed questionnaires assessing their vaccination attitudes, behavioural intentions, and moral preferences. Using Latent Profile Analysis, we identified three profiles (i.e., groups), interpretable as vaccine "accepters", "fence sitters", and "rejecters", each characterised by a distinct pattern of vaccination attitudes and moral preferences. Accepters exhibited positive vaccination attitudes and strong intentions to vaccinate; rejecters exhibited the opposite pattern of responses; whilst fence sitters exhibited an intermediate pattern of responses. Compared to accepters, rejecters and fence sitters exhibited a heightened moral preference for liberty (belief in the rights of the individual) and harm (concern about the wellbeing of others). Compared to acceptors and fence sitters, rejecters exhibited a heightened moral preference for purity (an abhorrence for impurity of body), and a diminished moral preference for authority (deference to those in positions of power). Given the sensitivity of fence sitters and rejecters to liberty-related moral concerns, our research cautions against the use of adversarial approaches-e.g., No Jab, No Pay legislation-that promote vaccination uptake by restricting parental freedoms, as they may backfire amongst parents ambivalent toward vaccination.


Reduction in left supplementary motor area grey matter in adult female fibromyalgia sufferers with marked fatigue and without affective disorder: a pilot controlled 3-T magnetic resonance imaging voxel-based morphometry study.
This study aimed to test the hypothesis that structural grey matter brain changes might occur in the chronic intractable pain disorder fibromyalgia when this is associated with marked fatigue in the absence of a DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision) diagnosis of affective disorder. High-resolution 3-T cerebral magnetic resonance imaging scans were acquired in 10 female, right-handed, non-smoking, white Caucasian subjects: five patients with fibromyalgia associated with marked fatigue and five age-matched healthy women. Voxel-wise generalized linear modelling of the processed neuroanatomical data using permutation-based non-parametric testing, forming clusters at t > 2.3 and testing clusters for significance at P < 0.05, corrected for multiple comparisons across space, revealed significantly lower grey matter density in the patients with fibromyalgia and marked fatigue in the left supplementary motor area. This brain region plays an important role in cognitive or executive control and in the translation of painful cognition; these functions are impaired in fibromyalgia associated with marked fatigue.


A Manifold Regularized Multi-Task Learning Model for IQ Prediction From Two fMRI Paradigms.
Multi-modal brain functional connectivity (FC) data have shown great potential for providing insights into individual variations in behavioral and cognitive traits. The joint learning of multi-modal data can utilize intrinsic association, and thus can boost learning performance. Although several multi-task based learning models have already been proposed by viewing feature learning on each modality as one task, most of them ignore the structural information inherent across the modalities, which may play an important role in extracting discriminative features. In this paper, we propose a new manifold regularized multi-task learning model by simultaneously considering between-subject and between-modality relationships. Specifically, the l2,1-norm (i.e., group-sparsity) regularizer is enforced to jointly select a few common features across different modalities. A novelly designed manifold regularizer is further imposed as a crucial underpinning to preserve the structural information both within and between modalities. Such designed regularizers will make our model more adaptive to realistic neuroimaging data, which are usually of small sample size but high dimensional features. Our model is validated on the Philadelphia Neurodevelopmental Cohort dataset, where our modalities are regarded as two types of functional MRI (fMRI) data collected under two paradigms. We conduct experimental studies on fMRI-based FC network data in two task conditions for intelligence quotient (IQ) prediction. The results show that our proposed model can not only achieve improved prediction performance, but also yield a set of IQ-relevant biomarkers. This paper develops a new multi-task learning model, enabling the discovery of significant biomarkers that may account for a proportion of the variance in human intelligence.


Distinct perceptual grouping pathways revealed by temporal carriers and envelopes.
S. E. Guttman, L. A. Gilroy, and R. Blake (2005) investigated whether observers could perform temporal grouping in multi-element displays where each local element was stochastically modulated over time along one of several potential dimensions--or "messenger types"--such as contrast, position, orientation, or spatial scale. Guttman et al.'s data revealed that grouping discards messenger type and therefore support a single-pathway model that groups elements with similar temporal waveforms. In the current study, we carried out three experiments in which temporal-grouping information resided either in the carrier, the envelope, or the combined carrier and envelope of each messenger's timecourse. Results revealed that grouping is highly specific for messenger type if carrier envelopes lack grouping information but largely messenger nonspecific if carrier envelopes contain grouping information. These imply that temporal grouping is mediated by several messenger-specific carrier pathways as well as by a messenger-nonspecific envelope pathways. Findings also challenge simple temporal-filtering accounts of perceptual grouping (E. H. Adelson & H. Farid, 1999).


Variability of the response to immunotherapy among subgroups of patients with multiple sclerosis.
This study assessed the effect of patient characteristics on the response to disease-modifying therapy (DMT) in multiple sclerosis (MS). We extracted data from 61,810 patients from 135 centers across 35 countries from the MSBase registry. The selection criteria were: clinically isolated syndrome or definite MS, follow-up ≥ 1 year, and Expanded Disability Status Scale (EDSS) score ≥ 3, with ≥1 score recorded per year. Marginal structural models with interaction terms were used to compare the hazards of 12-month confirmed worsening and improvement of disability, and the incidence of relapses between treated and untreated patients stratified by their characteristics. Among 24,344 patients with relapsing MS, those on DMTs experienced 48% reduction in relapse incidence (hazard ratio [HR] = 0.52, 95% confidence interval [CI] = 0.45-0.60), 46% lower risk of disability worsening (HR = 0.54, 95% CI = 0.41-0.71), and 32% greater chance of disability improvement (HR = 1.32, 95% CI = 1.09-1.59). The effect of DMTs on EDSS worsening and improvement and the risk of relapses was attenuated with more severe disability. The magnitude of the effect of DMT on suppressing relapses declined with higher prior relapse rate and prior cerebral magnetic resonance imaging activity. We did not find any evidence for the effect of age on the effectiveness of DMT. After inclusion of 1985 participants with progressive MS, the effect of DMT on disability mostly depended on MS phenotype, whereas its effect on relapses was driven mainly by prior relapse activity. DMT is generally most effective among patients with lower disability and in relapsing MS phenotypes. There is no evidence of attenuation of the effect of DMT with age.


Managing fertile women under lithium treatment: the challenge of a Teratology Information Service.
The objective of the present study is to review the literature regarding the management of fertile patients under lithium treatment for bipolar disorder and to report the experience of our Teratology Information Service over the past thirteen years in managing women treated with lithium during preconception, pregnancy and breastfeeding. This research focuses on a selective review of the literature and a retrospective survey has been carried out on fertile women under lithium treatment who called our service at A. Gemelli University Hospital in Rome from May 2002 to December 2015. A total of 140 women under lithium treatment called our TIS. A complete follow-up has been performed on 34 patients: 29 called during pregnancy and 5 called during preconception. None of the patients called during breastfeeding, while half of the patients were taking concomitant drugs during pregnancy. One major cardiac malformation (hypoplastic left heart syndrome) has been reported. No minor malformations have been detected. Twenty-one patients delivered a living child, with one premature neonate. Two patients underwent voluntary interruption of pregnancy and six patients had early spontaneous abortion. In one patient, intrauterine growth retardation occurred, but with no adverse neonatal outcomes. Four neonates experienced transient respiratory distress at birth. Two children developed mild to severe language delay, but normal motor development. Lithium treatment in fertile women is a very delicate topic, where risks and benefits of discontinuing therapy when women plan to become pregnant should be accurately evaluated. Thorough peri-conceptional counselling is crucial for the outcome of pregnancy and for maternal health status during preconception, gestation and breastfeeding.


Effect of RSV bronchiolitis practice guidelines on resource utilization.
We sought to determine whether institution of respiratory syncytial virus (RSV) practice guidelines decreased resource utilization for a heterogeneous population of children hospitalized with RSV bronchiolitis. Patients less than 24 months old with RSV bronchiolitis at a pediatric referral center were identified by retrospective chart review for consecutive RSV seasons. Before the guidelines were instituted patients were less likely to have a documented physician's assessment of response to albuterol, were more likely to have received supplemental oxygen and cardiorespiratory monitoring, and to be discharged on an albuterol regimen. Patients received more albuterol treatments. After the guidelines were in place fewer resources were utilized in the care of patients with RSV bronchiolitis. RSV practice guidelines may simplify and streamline the care of a heterogeneous population of children with bronchiolitis.


Comparison of Lumbar Kinematics with a History of Low Back Pain During Baseball Hitting.
The purpose of this study was to examine the influence of a history of low back pain (LBP) on pelvic and lumbar kinematics during baseball hitting. Twenty collegiate male baseball players (age, 21±1 years; height, 172.8±4.7 cm; weight, 72.7±6.2 kg; baseball experience, 13±1 years) performed 5 bat swings. Participants were categorized into the LBP group (n=10) or control group (n=10) based on having experienced lumbar spine pain due to bat swing that lasted more than 24 h within the last 12 months. Three-dimensional kinematic data of the pelvis and lumbar spine during bat swing were measured. Two-way ANOVAs were used to compare pelvic and lumbar kinematics throughout the bat swing between groups, and independent t-tests were used to compare the other outcomes between groups. There was a significant main effect between groups in lumbar flexion angle throughout the bat swing (p=0.047). The mean lumbar flexion angle of the LBP group throughout the bat swing was less than that of the control group. Additionally, the peak angular velocity of lumbar flexion of the LBP group was significantly faster than that of control group (p=0.047). These results can be helpful for longitudinal studies that identify the risk factors of LBP due to bat swing.


Metabolic adaptation to a high-fat diet is associated with a change in the gut microbiota.
The gut microbiota, which is considered a causal factor in metabolic diseases as shown best in animals, is under the dual influence of the host genome and nutritional environment. This study investigated whether the gut microbiota per se, aside from changes in genetic background and diet, could sign different metabolic phenotypes in mice. The unique animal model of metabolic adaptation was used, whereby C57Bl/6 male mice fed a high-fat carbohydrate-free diet (HFD) became either diabetic (HFD diabetic, HFD-D) or resisted diabetes (HFD diabetes-resistant, HFD-DR). Pyrosequencing of the gut microbiota was carried out to profile the gut microbial community of different metabolic phenotypes. Inflammation, gut permeability, features of white adipose tissue, liver and skeletal muscle were studied. Furthermore, to modify the gut microbiota directly, an additional group of mice was given a gluco-oligosaccharide (GOS)-supplemented HFD (HFD+GOS). Despite the mice having the same genetic background and nutritional status, a gut microbial profile specific to each metabolic phenotype was identified. The HFD-D gut microbial profile was associated with increased gut permeability linked to increased endotoxaemia and to a dramatic increase in cell number in the stroma vascular fraction from visceral white adipose tissue. Most of the physiological characteristics of the HFD-fed mice were modulated when gut microbiota was intentionally modified by GOS dietary fibres. The gut microbiota is a signature of the metabolic phenotypes independent of differences in host genetic background and diet.


Testing for the existence of clusters.
Detecting and determining clusters present in a certain sample has been an important concern, among researchers from different fields, for a long time. In particular, assessing whether the clusters are statistically significant, is a question that has been asked by a number of experimenters. Recently, this question arose again in a study in maize genetics, where determining the significance of clusters is crucial as a primary step in the identification of a genome-wide collection of mutants that may affect the kernel composition.Although several efforts have been made in this direction, not much has been done with the aim of developing an actual hypothesis test in order to assess the significance of clusters. In this paper, we propose a new methodology that allows the examination of the hypothesis test H(0) : κ=1 vs. H(1) : κ=k, where κ denotes the number of clusters present in a certain population. Our procedure, based on Bayesian tools, permits us to obtain closed form expressions for the posterior probabilities corresponding to the null hypothesis. From here, we calibrate our results by estimating the frequentist null distribution of the posterior probabilities in order to obtain the p-values associated with the observed posterior probabilities. In most cases, actual evaluation of the posterior probabilities is computationally intensive and several algorithms have been discussed in the literature. Here, we propose a simple estimation procedure, based on MCMC techniques, that permits an efficient and easily implementable evaluation of the test. Finally, we present simulation studies that support our conclusions, and we apply our method to the analysis of NIR spectroscopy data coming from the genetic study that motivated this work.


Caudate nucleus dopamine D(2) receptors in depressed suicide victims.
Several lines of evidence indicate the involvement of the dopamine system in depressive states. In this post-mortem study, the binding of [(3)H]raclopride to dopamine D(2) receptors in the caudate nucleus was investigated in 13 depressed suicide victims and 19 controls. There were no differences in B(max) or K(d) between the two groups. A subgroup consisting of individuals with major depression, however, had significantly higher K(d) values than controls. Previous findings regarding changes in dopamine metabolism in depression and antidepressant effects of dopamine agonists seem, according to the present study, not to be reflected by alterations in density or affinity of dopamine D(2) receptors in depressed suicide victims.


Linear systems modeling of adaptive optics in the spatial-frequency domain.
Spatial-frequency domain techniques have traditionally been applied to obtain estimates for the independent effects of a variety of individual error sources in adaptive optics (AO). Overall system performance is sometimes estimated by introducing the approximation that these individual error terms are statistically independent, so that their magnitudes may be summed in quadrature. More accurate evaluation methods that account for the correlations between the individual error sources have required Monte Carlo simulations or large matrix calculations that can take much longer to compute, particularly as the order of the AO system increases beyond a few hundred degrees of freedom. We describe an approach to evaluating AO system performance in the spatial-frequency domain that is relatively computationally efficient but still accounts for many of the interactions between the fundamental error sources in AO. We exploit the fact that (in the limits of an infinite aperture and geometrical optics) all the basic wave-front propagation, sensing, and correction processes that describe the behavior of an AO system are spatial-filtering operations in the Fourier domain. Essentially all classical wave-front control algorithms and evaluation formulas are expressed in terms of these filters and may therefore be evaluated one spatial-frequency component at a time. Performance estimates for very-high-order AO systems may be obtained in 1 to 2 orders of magnitude less time than needed when detailed simulations or analytical models in the spatial domain are used, with a relative discrepancy of 5% to 10% for typical sample problems.


DNA copy number motifs are strong and independent predictors of survival in breast cancer.
Somatic copy number alterations are a frequent sign of genome instability in cancer. A precise characterization of the genome architecture would reveal underlying instability mechanisms and provide an instrument for outcome prediction and treatment guidance. Here we show that the local spatial behavior of copy number profiles conveys important information about this architecture. Six filters were defined to characterize regional traits in copy number profiles, and the resulting Copy Aberration Regional Mapping Analysis (CARMA) algorithm was applied to tumors in four breast cancer cohorts (n = 2919). The derived motifs represent a layer of information that complements established molecular classifications of breast cancer. A score reflecting presence or absence of motifs provided a highly significant independent prognostic predictor. Results were consistent between cohorts. The nonsite-specific occurrence of the detected patterns suggests that CARMA captures underlying replication and repair defects and could have a future potential in treatment stratification.


Fragmentation of daily rhythms associates with obesity and cardiorespiratory fitness in adolescents: The HELENA study.
Chronobiology studies periodic changes in living organisms and it has been proposed as a promising approach to investigate obesity. We analyze the association of the characteristics of the rest-activity rhythms with obesity, cardiorespiratory fitness and metabolic risk in adolescents from nine European countries. 1044 adolescents (12.5-17.5 y) were studied. Circadian health was evaluated by actigraphy with accelerometers (Actigraph GT1M). Characteristics of the daytime activity such as fragmentation (intradaily variability), estimated acrophase, and 10 h mean daytime activity index were obtained. Body composition was assessed using Bioelectrical-Impedance-Analysis, skinfold thickness, air-displacement-plethysmography and Dual-energy-X-ray-Absorptiometry. Cardiorespiratory fitness (VO2max) and metabolic risk were studied. Highly fragmented activity rhythms were associated with obesity and central adiposity (P < 0.05). Obese adolescents had ∼3 times higher odds of having a high fragmentation of daytime activity compared to normal weight adolescents OR (95% CI) = 2.8 (1.170, 6.443). A highly fragmented rhythm was also related to lower cardiorespiratory fitness and higher metabolic risk (P < 0.05) so those adolescents classified as low fitness showed a significantly higher fragmentation of daytime activity than those included in the high fitness group (P < 0.0001). Other characteristics of the rhythms such as smaller 10 h daytime mean activity index and delayed estimated acrophase were also related to obesity and metabolic risk (P < 0.05). Our results indicate that the daily organization of the rest-activity cycle is more fragmented in obese and less fit adolescents and correlates with higher metabolic risk. This fact reinforces our hypothesis that disturbances in daily rhythms can be considered as sensitive markers of poorer adolescent's health.


Ameloblastin, an Extracellular Matrix Protein, Affects Long Bone Growth and Mineralization.
Matrix molecules such as the enamel-related calcium-binding phosphoprotein ameloblastin (AMBN) are expressed in multiple tissues, including teeth, bones, and cartilage. Here we have asked whether AMBN is of functional importance for timely long bone development and, if so, how it exerts its function related to osteogenesis. Adolescent AMBN-deficient mice (AMBN(Δ5-6) ) suffered from a 33% to 38% reduction in femur length and an 8.4% shorter trunk spinal column when compared with WT controls, whereas there was no difference between adult animals. On a cellular level, AMBN truncation resulted in a shortened growth plate and a 41% to 49% reduction in the number of proliferating tibia chondrocytes and osteoblasts. Bone marrow stromal cells (BMSCs) isolated from AMBN mutant mice displayed defects in proliferation and differentiation potential as well as cytoskeleton organization. Osteogenesis-related growth factors, such as insulin-like growth factor 1 (IGF1) and BMP7, were also significantly (46% to 73%) reduced in AMBN-deficient BMSCs. Addition of exogenous AMBN restored cytoskeleton structures in AMBN mutant BMSCs and resulted in a dramatic 400% to 600% increase in BMP2, BMP7, and Col1A expression. Block of RhoA diminished the effect of AMBN on osteogenic growth factor and matrix protein gene expression. Addition of exogenous BMP7 and IGF1 rescued the proliferation and differentiation potential of AMBN-deficient BMSCs. Confirming the effects of AMBN on long bone growth, back-crossing of mutant mice with full-length AMBN overexpressors resulted in a complete rescue of AMBN(Δ5-6) bone defects. Together, these data indicate that AMBN affects extracellular matrix production and cell adhesion properties in the long bone growth plate, resulting in altered cytoskeletal dynamics, increased osteogenesis-related gene expression, as well as osteoblast and chondrocyte proliferation. We propose that AMBN facilitates rapid long bone growth and an important growth spurt during the skeletogenesis of adolescent tooth-bearing vertebrates. © 2016 American Society for Bone and Mineral Research.


Hyphal orientation of Candida albicans is regulated by a calcium-dependent mechanism.
Eukaryotic cells from fungal hyphae to neurites that grow by polarized extension must coordinate cell growth and cell orientation to enable them to exhibit growth tropisms and to respond to relevant environmental cues. Such cells generally maintain a tip-high Ca(2+) cytoplasmic gradient, which is correlated with their ability to exhibit polarized tip growth and to respond to growth-directing extracellular signals. In yeast and other fungi, the polarisome, exocyst, Arp2/3, and Spitzenkörper protein complexes collectively orchestrate tip growth and cell polarity, but it is not clear whether these molecular complexes also regulate cell orientation or whether they are influenced by cytoplasmic Ca(2+) gradients. Hyphae of the human pathogenic fungus Candida albicans reorient their growth axis in response to underlying surface topography (thigmotropism) and imposed electric fields (galvanotropism). The establishment and maintenance of directional growth in relation to these environmental cues was Ca(2+) dependent. Tropisms were attenuated in media containing low Ca(2+), or calcium-channel blockers, and in mutants where calcium channels or elements of the calcium signaling pathway were deleted. Therefore galvanotropism and thigmotropism may both be mediated by localized Ca(2+) influx at sites of polarized growth via Ca(2+) channels that are activated by appropriate environmental signals.


Clinical significance of CXC chemokine receptor-4 and c-Met in childhood rhabdomyosarcoma.
The CXC chemokine receptor-4 (CXCR4)/stromal-derived factor-1 and c-Met/hepatocyte growth factor axes promote the metastatic potential of rhabdomyosarcoma cell lines in experimental models, but no data are available on their role in rhabdomyosarcoma tumors. The expressions of CXCR4 and c-Met were evaluated in primary tumors and isolated tumor cells in marrow, and were correlated with clinicopathologic variables and survival. Forty patients with recently diagnosed rhabdomyosarcoma were retrospectively enrolled. CXCR4 and c-Met expression was investigated in primary tumors by immunohistochemistry, in isolated marrow-infiltrating tumor cells using double-label immunocytology. Results were expressed as the mean percentage of immunostained tumor cells. CXCR4 and c-Met were expressed in >/=5% of tumor cells from 40 of 40 tumors, with 14 of 40 cases showing >/=50% of immunostained tumor cells (high expression). High CXCR4 expression correlated with alveolar histology (P = 0.006), unfavorable primary site (P = 0.009), advanced group (P < 0.001), marrow involvement (P = 0.007), and shorter overall survival and event-free survival (P < 0.001); high c-Met expression correlated with alveolar histology (P = 0.005), advanced group (P = 0.04), and marrow involvement (P = 0.02). In patients with a positive diagnosis for isolated tumor cells in marrow (n = 16), a significant enrichment in the percentage of CXCR4-positive (P = 0.001) and c-Met-positive (P = 0.003) tumor cells was shown in marrow aspirates compared with the corresponding primary tumors. CXCR4 and c-Met are widely expressed in both rhabdomyosarcoma subtypes and, at higher levels, in isolated marrow-infiltrating tumor cells. High levels of expression are associated with unfavorable clinical features, tumor marrow involvement and, only for CXCR4, poor outcome. In rhabdomyosarcoma, CXCR4 and c-Met represent novel exploitable targets for disease-directed therapy.


Abstract reward and punishment representations in the human orbitofrontal cortex.
The orbitofrontal cortex (OFC) is implicated in emotion and emotion-related learning. Using event-related functional magnetic resonance imaging (fMRI), we measured brain activation in human subjects doing an emotion-related visual reversal-learning task in which choice of the correct stimulus led to a probabilistically determined 'monetary' reward and choice of the incorrect stimulus led to a monetary loss. Distinct areas of the OFC were activated by monetary rewards and punishments. Moreover, in these areas, we found a correlation between the magnitude of the brain activation and the magnitude of the rewards and punishments received. These findings indicate that one emotional involvement of the human orbitofrontal cortex is its representation of the magnitudes of abstract rewards and punishments, such as receiving or losing money.


Long-Term Follow-Up of Ibrutinib Monotherapy in Symptomatic, Previously Treated Patients With Waldenström Macroglobulinemia.
We report the long-term findings and final analysis of a pivotal multicenter trial of ibrutinib monotherapy in previously treated patients with Waldenström macroglobulinemia (WM). Sixty-three symptomatic patients with median prior therapies of two (range, one to nine therapies), of whom 40% were refractory to their previous therapy, received ibrutinib at 420 mg/d. Dose reduction was permitted for toxicity. The median follow-up was 59 months, and overall and major response rates were 90.5% and 79.4%, respectively. At best response, median serum immunoglobulin M declined from 3,520 to 821 mg/dL, bone marrow disease involvement declined from 60% to 20%, and hemoglobin rose from 10.3 to 14.2 g/dL (P < .001 for all comparisons). Responses were impacted by mutated (Mut) MYD88 and CXCR4 status. Patients with MYD88Mut, wild-type (WT) CXCR4 showed higher major (97.2% v 68.2%; P < .0001) and very good partial (47.2% v 9.1%; P < .01) response rates and a shorter time to major response (1.8 v 4.7 months; P = .02) versus patients with MYD88MutCXCR4Mut. Conversely, four patients who had MYD88WT disease showed no major responses. The median 5-year progression-free survival (PFS) rate for all patients was not reached, and was 70% and 38% for those with MYD88MutCXCR4WT and MYD88MutCXCR4Mut WM, respectively (P = .02). In patients with MYD88WT, the median PFS was 0.4 years (P < .01 for three-way comparisons). The 5-year overall survival rate for all patients was 87%. Grade ≥ 3 adverse events in more than one patient at least possibly related included neutropenia (15.9%), thrombocytopenia (11.1%), and pneumonia (3.2%). Eight patients (12.7%) experienced atrial arrhythmia, and seven of the eight continued therapy with medical management. Ibrutinib is highly active and produces long-term disease control in previously treated patients with WM. Treatment is tolerable. Response depth, time to major response, and PFS are impacted by MYD88 and CXCR4 mutation status.


Direct generation of a multi-transverse mode non-classical state of light.
Quantum computation and communication protocols require quantum resources which are in the continuous variable regime squeezed and/or quadrature entangled optical modes. To perform more and more complex and robust protocols, one needs sources that can produce in a controlled way highly multimode quantum states of light. One possibility is to mix different single mode quantum resources. Another is to directly use a multimode device, either in the spatial or in the frequency domain. We present here the first experimental demonstration of a device capable of producing simultaneously several squeezed transverse modes of the same frequency and which is potentially scalable. We show that this device, which is an Optical Parametric Oscillator using a self-imaging cavity, produces a multimode quantum resource made of three squeezed transverse modes.


Increased neutrophil extracellular trap-mediated Staphylococcus aureus clearance through inhibition of nuclease activity by clindamycin and immunoglobulin.
The Gram-positive human pathogen Staphylococcus aureus causes a variety of human diseases such as skin infections, pneumonia, and endocarditis. The micrococcal nuclease Nuc1 is one of the major S. aureus virulence factors and allows the bacterium to avoid neutrophil extracellular trap (NET)-mediated killing. We found that addition of the protein synthesis inhibitor clindamycin to S. aureus LAC cultures decreased nuc1 transcription and subsequently blunted nuclease activity in a molecular beacon-based fluorescence assay. We also observed reduced NET degradation through Nuc1 inhibition translating into increased NET-mediated clearance. Similarly, pooled human immunoglobulin specifically inhibited nuclease activity in a concentration-dependent manner. Inhibition of nuclease activity by clindamycin and immunoglobulin enhanced S. aureus clearance and should be considered in the treatment of S. aureus infections.


Methodological problems in evaluation of cardiovascular effects of stress in humans.
Cardiovascular effects of stress in humans are often assessed by application of physical or emotional stimuli in a laboratory environment. Although this method provides important information, these procedures have several limitations. First, blood pressure and heart rate responses to laboratory stressors are characterized by a limited within-subject reproducibility. Second, there is poor correlation between blood pressure and heart rate responses to different stressors, which implies that individual reaction to stress may be estimated differently according to the test used. Finally, these responses bear only a limited relation to 24-hour or daytime blood pressure variability, that is, they reflect to only a limited extent the tendency of blood pressure to vary during daily activities. If assessed by techniques that allow blood pressure to be continuously recorded for 24 hours in ambulatory subjects, blood pressure variability represents a possible approach to observation of cardiovascular reactivity away from an artificial laboratory environment. However, whether blood pressure variability should be expressed as a percentage or in absolute values is controversial. Furthermore, although naturally occurring stress may markedly increase blood pressure, 24-hour blood pressure variations also depend on factors that are not related to emotional stimuli. Thus, the study of cardiovascular responses to stress in humans encounters several problems, regardless of the method used.


Comparison of paper print and soft copy reading in plain paediatric radiographs.
With the introduction of a Picture Archiving and Communication System, Computed (CR) and Digital Radiography (DR), reading digital images takes place from a computer screen. Laser paper print rather than laser film would be a significantly more cost-effective option for hard copy production, but would need to demonstrate acceptable diagnostic quality compared to the reference standard of screen reading. A comparative study of 51 digital paediatric CR radiographs presented in laser paper print and soft copy format to determine the diagnostic value of the paper print when compared to the reference standard of screen reading. Chest radiography had a poor sensitivity of 66.1% while musculoskeletal and abdominal radiography had acceptable sensitivities of 90% and 99%, respectively. Specificity was excellent for the different regions (98.6-99.5%). The paper print format should not be used for diagnostic purposes in paediatric chest radiography, but may still be used for demonstration when accompanied by the radiology rapport obtained from soft copy reading. Further studies would be needed to investigate the use of paper prints in abdominal and musculoskeletal radiography owing to the low number of abdominal radiographs and lack of musculoskeletal case variety in our study.


Major differences in the behaviour of carbon paste and carbon fibre electrodes in a protein-lipid matrix: implications for voltammetry in vivo.
The widely documented differences in behaviour of carbon fibre electrodes (CFEs) and carbon paste electrodes (CPEs) used for neurochemical analysis in vivo were investigated. Differential staircase voltammetry was used to study the electrooxidation of ascorbic acid (AA) at CFEs and CPEs in the presence of major constituents of brain tissue, viz., protein, lipid or a mixture of both. Both electrode types were poisoned by protein, reflected in positive shifts in the AA voltammetric peak potential, and also peak broadening, following exposure of the electrodes to protein solution. In contrast, CFEs and CPEs responded very differently to exposure to lipid suspension: CFEs exhibited poisoning whereas CPEs showed enhanced electron transfer kinetics for AA. This significant difference in the response of the two carbon materials to lipid was further demonstrated by showing that lipid could reverse the poisoning caused by protein for CPEs but not CFEs. It appears, therefore, that proteins adsorb on both CPEs and CFEs, hindering electron transfer from AA to the electrode surface. Surfactant lipid molecules, in contrast, have a cleaning effect on CPEs, removing pasting oil and adsorbed proteins from the CPE surface. These results provide an explanation for the stability of CPEs in brain tissue and for the contrasting instability of CFEs in the same environment. The data also suggest that a lipid-protein matrix represents a valuable in vitro chemical model of brain tissue that should allow a truer characterisation in vitro of new and existing in vivo sensors, reducing the need for animal experiments in these studies.


Do pressures to publish increase scientists' bias? An empirical support from US States Data.
The growing competition and "publish or perish" culture in academia might conflict with the objectivity and integrity of research, because it forces scientists to produce "publishable" results at all costs. Papers are less likely to be published and to be cited if they report "negative" results (results that fail to support the tested hypothesis). Therefore, if publication pressures increase scientific bias, the frequency of "positive" results in the literature should be higher in the more competitive and "productive" academic environments. This study verified this hypothesis by measuring the frequency of positive results in a large random sample of papers with a corresponding author based in the US. Across all disciplines, papers were more likely to support a tested hypothesis if their corresponding authors were working in states that, according to NSF data, produced more academic papers per capita. The size of this effect increased when controlling for state's per capita R&D expenditure and for study characteristics that previous research showed to correlate with the frequency of positive results, including discipline and methodology. Although the confounding effect of institutions' prestige could not be excluded (researchers in the more productive universities could be the most clever and successful in their experiments), these results support the hypothesis that competitive academic environments increase not only scientists' productivity but also their bias. The same phenomenon might be observed in other countries where academic competition and pressures to publish are high.


Γ-Al₂O₃-based nanocomposite adsorbents for arsenic(V) removal: assessing performance, toxicity and particle leakage.
The generation and development of effective adsorption materials for arsenic removal are urgently needed due to acute arsenic contamination of water sources in many regions around the world. In the search for these new adsorbents, the application of nanomaterials or nanocomposites, and especially the use of nanoparticles (NPs), has proven increasingly attractive. While the adsorptive performance of a range of nanocomposite and nanomaterial-based systems has been extensively reviewed in previously-published literature, the stability of these systems in terms of NP release, i.e. the ability of the nanomaterial or nanocomposite to retain incorporated NPs, is less well understood. Here we examine the performance of nanocomposites comprised of aluminium oxide nanoparticles (AluNPs) incorporated in macroporous polyacrylamide-based cryogels (n-Alu-cryo, where n indicates the percentage of AluNPs in the polymer material (n=0-6%, w/v)) for As(V) adsorption, and evaluate AluNP leakage before and after the use of these materials. A range of techniques is utilised and assessed (SEM, TEM, mass weight change, PIXE and in vitro toxicity studies). The 4-Alu-cryo nanocomposite was shown to be optimal for minimising AluNP losses while maximising As(V) removal. From the same nanocomposite we were further able to show that NP losses were not detectable at the AluNP concentrations used in the study. Toxicity tests revealed that no cytotoxic effects could be observed. The cryogel-AluNPs composites were not only effective in As(V) removal but also in immobilising the AluNPs. More challenging flow-through conditions for the evaluation of NP leakage could be included as a next step in a continued study assessing particle loss and subsequent toxicity.


Interplay of Histone Marks with Serine ADP-Ribosylation.
Serine ADP-ribosylation (Ser-ADPr) is a recently discovered protein modification that is catalyzed by PARP1 and PARP2 when in complex with the eponymous histone PARylation factor 1 (HPF1). In addition to numerous other targets, core histone tails are primary acceptors of Ser-ADPr in the DNA damage response. Here, we show that specific canonical histone marks interfere with Ser-ADPr of neighboring residues and vice versa. Most notably, acetylation, but not methylation of H3K9, is mutually exclusive with ADPr of H3S10 in vitro and in vivo. We also broaden the O-linked ADPr spectrum by providing evidence for tyrosine ADPr on HPF1 and other proteins. Finally, we facilitate wider investigations into the interplay of histone marks with Ser-ADPr by introducing a simple approach for profiling posttranslationally modified peptides. Our findings implicate Ser-ADPr as a dynamic addition to the complex interplay of modifications that shape the histone code.


Genetic evidence for high propagule pressure and long-distance dispersal in monk parakeet (Myiopsitta monachus) invasive populations.
The monk parakeet (Myiopsitta monachus) is a successful invasive species that does not exhibit life history traits typically associated with colonizing species (e.g., high reproductive rate or long-distance dispersal capacity). To investigate this apparent paradox, we examined individual and population genetic patterns of microsatellite loci at one native and two invasive sites. More specifically, we aimed at evaluating the role of propagule pressure, sexual monogamy and long-distance dispersal in monk parakeet invasion success. Our results indicate little loss of genetic variation at invasive sites relative to the native site. We also found strong evidence for sexual monogamy from patterns of relatedness within sites, and no definite cases of extra-pair paternity in either the native site sample or the examined invasive site. Taken together, these patterns directly and indirectly suggest that high propagule pressure has contributed to monk parakeet invasion success. In addition, we found evidence for frequent long-distance dispersal at an invasive site (approximately 100 km) that sharply contrasted with previous estimates of smaller dispersal distance made in the native range (approximately 2 km), suggesting long-range dispersal also contributes to the species' spread within the United States. Overall, these results add to a growing body of literature pointing to the important role of propagule pressure in determining, and thus predicting, invasion success, especially for species whose life history traits are not typically associated with invasiveness.


Rayleigh scattering boosted multi-GHz displacement sensitivity in whispering gallery opto-mechanical resonators.
Finite photon lifetimes for light fields in an opto-mechanical cavity impose a bandwidth limit on displacement sensing at mechanical resonance frequencies beyond the loaded cavity photon decay rate. Opto-mechanical modulation efficiency can be enhanced via multi-GHz transduction techniques such as piezo-opto-mechanics at the cost of on-chip integration. In this paper, we present a novel high bandwidth displacement sense scheme employing Rayleigh scattering in photonic resonators. Using this technique in conjunction with on-chip electrostatic drive in silicon enables efficient modulation at frequencies up to 9.1GHz. Being independent of the drive mechanism, this scheme could readily be extended to piezo-opto-mechanical and all optical transduced systems.


Substance use and periodontal disease among Australian Aboriginal young adults.
To investigate the effects of tobacco, marijuana, alcohol and petrol sniffing on periodontal disease among Australian Aboriginal young adults. Cross-sectional nested within a long-standing prospective longitudinal study. Setting Aboriginal communities in Australia's Northern Territory. Members of the Aboriginal Birth Cohort study who were recruited from birth between January 1987 and March 1990 at the Royal Darwin Hospital, Northern Territory, Australia. Data were from wave III, when the mean age of participants was 18 years. Clinical dental examination and self-report questionnaire. Of 425 participants with complete data, 26.6% had moderate/severe periodontal disease. There was elevated risk of periodontal disease associated with tobacco [prevalence ratio (PR) = 1.59, 95% CI = 1.06-2.40], marijuana (PR = 1.44, 95% CI = 1.05-1.97) and petrol sniffing (PR = 1.83, 95% CI = 1.08-3.11), but not alcohol (PR = 0.92, 95% CI = 0.67-1.27). Stratified analysis showed that the effect of marijuana persisted among tobacco users (PR = 1.47, 95% CI 1.03-2.11). It was not possible to isolate an independent effect of petrol sniffing because all petrol sniffers used both marijuana and tobacco, although among smokers of both substances, petrol sniffing was associated with an 11.8% increased prevalence of periodontal disease. This is the first time that substance use has been linked with periodontal disease in a young Australian Aboriginal adult population, and the first time that petrol sniffing has been linked with periodontal disease in any population. The role of substance use in periodontal disease among this, and other, marginalized groups warrants further investigation.


Attractive toxic sugar baits: control of mosquitoes with the low-risk active ingredient dinotefuran and potential impacts on nontarget organisms in Morocco.
We evaluated the efficacy of attractive toxic sugar baits (ATSB) in the laboratory and field with the low-risk active ingredient dinotefuran against mosquito populations. Preliminary laboratory assays indicated that dinotefuran in solution with the sugar baits was ingested and resulted in high mortality of female Culex quinquefasciatus Say and Aedes aegypti Linnaeus. Field studies demonstrated >70% reduction of mosquito populations at 3 wk post-ATSB application. Nontarget feeding of seven insect orders-Hymenoptera, Lepidoptera, Coleoptera, Diptera, Hemiptera, Orthoptera, and Neuroptera-was evaluated in the field after application of attractive sugar baits (ASB) on vegetation by dissecting the guts and searching for food dye with a dissecting microscope. Nontargets were found stained with ASB 0.9% of the time when the application was applied on green nonflowering vegetation. Only two families were significantly impacted by the ASB application: Culicidae (mosquitoes) and Chironomidae (nonbiting midges) of the order Diptera. Pollinators of the other insect orders were not significantly impacted. No mortality was observed in the laboratory studies with predatory nontargets, wolf spiders or ground beetles, after feeding for 3 d on mosquitoes engorged on ATSB applied to vegetation. Overall, this novel control strategy had little impact on nontarget organisms, including pollinators and beneficial insects, and was effective at controlling mosquito populations, further supporting the development of ATSB for commercial use.


Interaction of silicon-based quantum dots with gibel carp liver: oxidative and structural modifications.
Quantum dots (QDs) interaction with living organisms is of central interest due to their various biological and medical applications. One of the most important mechanisms proposed for various silicon nanoparticle-mediated toxicity is oxidative stress. We investigated the basic processes of cellular damage by oxidative stress and tissue injury following QD accumulation in the gibel carp liver after intraperitoneal injection of a single dose of 2 mg/kg body weight Si/SiO2 QDs after 1, 3, and 7 days from their administration.QDs gradual accumulation was highlighted by fluorescence microscopy, and subsequent histological changes in the hepatic tissue were noted. After 1 and 3 days, QD-treated fish showed an increased number of macrophage clusters and fibrosis, while hepatocyte basophilia and isolated hepatolytic microlesions were observed only after substantial QDs accumulation in the liver parenchyma, at 7 days after IP injection.Induction of oxidative stress in fish liver was revealed by the formation of malondialdehyde and advanced oxidation protein products, as well as a decrease in protein thiol groups and reduced glutathione levels. The liver enzymatic antioxidant defense was modulated to maintain the redox status in response to the changes initiated by Si/SiO2 QDs. So, catalase and glutathione peroxidase activities were upregulated starting from the first day after injection, while the activity of superoxide dismutase increased only after 7 days. The oxidative damage that still occurred may impair the activity of more sensitive enzymes. A significant inhibition in glucose-6-phosphate dehydrogenase and glutathione-S-transferase activity was noted, while glutathione reductase remained unaltered.Taking into account that the reduced glutathione level had a deep decline and the level of lipid peroxidation products remained highly increased in the time interval we studied, it appears that the liver antioxidant defense of Carassius gibelio does not counteract the oxidative stress induced 7 days after silicon-based QDs exposure in an efficient manner.


Hydrogen-rich saline mediates neuroprotection through the regulation of endoplasmic reticulum stress and autophagy under hypoxia-ischemia neonatal brain injury in mice.
Hydrogen as a new medical gas exerts organ-protective effects through regulating oxidative stress, inflammation and apoptosis. Multiple lines of evidence reveal the protective effects of hydrogen in various models of brain injury. However, the exact mechanism underlying this protective effect of hydrogen against hypoxic-ischemic brain damage (HIBD) is not fully understood. The present study was designed to investigate whether hydrogen-rich saline (HS) attenuates HIBD in neonatal mice and whether the observed protection is associated with reduced endoplasmic reticulum (ER) stress and regulated autophagy. The results showed that HS treatment significantly improved brain edema and decreased infarct volume. Furthermore, HS significantly attenuated HIBD-induced ER stress responses, including the decreased expression of glucose-regulated protein 78, C/EBP homologous protein, and down-regulated transcription factor. Additionally, we demonstrated that HS induced autophagy, including increased LC3B and Beclin-1 expression and decreased phosphorylation of mTOR and Stat3, as well as phosphorylation of ERK. Taken together, HS exerts neuroprotection against HIBD in neonatal mouse, mediated in part by reducing ER stress and increasing autophagy machinery.


Induction of Diverse Cryptic Fungal Metabolites by Steroids and Channel Blockers.
Fungi offer a deep source of natural products but remain underutilized. Most biosynthetic gene clusters (BGCs) that can be detected are silent or "cryptic" in standard lab cultures and their products are thus not interrogated in routine screens. As genetic alterations are difficult and some strains can only be grown on agar, we have herein applied an agar-based high-throughput chemical genetic screen to identify inducers of fungal BGCs. Using R. solani and S. sclerotiorum as test cases, we report 13 cryptic metabolites in four compound groups, including sclerocyclane, a natural product with a novel scaffold. Steroids were the best elicitors and follow-up studies showed that plant-steroids trigger sclerocyclane synthesis, which shows antibiotic activity against B. plantarii, an ecological competitor of S. sclerotiorum. Our results open new paths to exploring the chemical ecology of fungal-plant interactions and provide a genetics-free approach for uncovering cryptic fungal metabolites.


Perceptual learning of second order cues for layer decomposition.
Luminance variations are ambiguous: they can signal changes in surface reflectance or changes in illumination. Layer decomposition-the process of distinguishing between reflectance and illumination changes-is supported by a range of secondary cues including colour and texture. For an illuminated corrugated, textured surface the shading pattern comprises modulations of luminance (first order, LM) and local luminance amplitude (second-order, AM). The phase relationship between these two signals enables layer decomposition, predicts the perception of reflectance and illumination changes, and has been modelled based on early, fast, feed-forward visual processing (Schofield et al., 2010). However, while inexperienced viewers appreciate this scission at long presentation times, they cannot do so for short presentation durations (250 ms). This might suggest the action of slower, higher-level mechanisms. Here we consider how training attenuates this delay, and whether the resultant learning occurs at a perceptual level. We trained observers to discriminate the components of plaid stimuli that mixed in-phase and anti-phase LM/AM signals over a period of 5 days. After training, the strength of the AM signal needed to differentiate the plaid components fell dramatically, indicating learning. We tested for transfer of learning using stimuli with different spatial frequencies, in-plane orientations, and acutely angled plaids. We report that learning transfers only partially when the stimuli are changed, suggesting that benefits accrue from tuning specific mechanisms, rather than general interpretative processes. We suggest that the mechanisms which support layer decomposition using second-order cues are relatively early, and not inherently slow.


Curvature of capillary bridges as a competition between wetting and confinement.
We consider the shape evolution of non-axisymmetric capillary bridges in slit pore geometry as the pore height is increased at constant volume. Experiments and finite element simulations using Surface Evolver have shown that as the height of the pore is increased the mean curvature of the bridge, and hence Laplace pressure, changes its sign from negative to positive. Here we propose an intuitive explanation of this surprising phenomenon. We suggest that it is the balance between the confinement and the wetting properties of the supporting strips that causes the change in sign of the Laplace pressure. The theory proposed relies on three simple approximations, which are tested individually, and is in good agreement with experiments and simulations in the regime where the curvature transition from negative to positive takes place. Theoretical arguments take into account only the wetting properties and geometry of the system (the width and height of the pore). Along with the formula for the curvature, we derive also a relation for the pinning angle of the capillary bridge, which is also verified experimentally.


The role of protons in fast and slow gating of the Torpedo chloride channel ClC-0.
Transmembrane proton transport is of fundamental importance for life. The list of H(+) transporting proteins has been recently expanded with the discovery that some members of the CLC gene family are stoichiometrically coupled Cl(-)/H(+) antiporters. Other CLC proteins are instead passive Cl(-) selective anion channels. The gating of these CLC channels is, however, strongly regulated by pH, likely reflecting the evolutionary relationship with CLC Cl(-)/H(+) antiporters. The role of protons in the gating of the model Torpedo channel ClC-0 is best understood. ClC-0 is a homodimer with separate pores in each subunit. Each protopore can be opened and closed independently from the other pore by a "fast gate". A common, slow gate acts on both pores simultaneously. The opening of the fast gate is controlled by a critical glutamate (E166), whose protonation state determines the fast gate's pH dependence. Extracellular protons likely can arrive directly at E166. In contrast, protonation of E166 from the inside has been proposed to be mediated by the dissociation of an intrapore water molecule. The OH(-) anion resulting from the water dissociation is stabilized in one of the anion binding sites of the channel, competing with intracellular Cl(-) ions. The pH dependence of the slow gate is less well understood. It has been shown that proton translocation drives irreversible gating transitions associated with the slow gate. However, the relationship of the fast gate's pH dependence on the proton translocation and the molecular basis of the slow gate remain to be discovered.


Herculin, a fourth member of the MyoD family of myogenic regulatory genes.
We have identified and cloned herculin, a fourth mouse muscle regulatory gene. Comparison of its DNA and deduced amino acid sequences with those of the three known myogenic genes (MyoD, myogenin, and Myf-5) reveals scattered short spans with similarity to one or more of these genes and a long span with strong similarity to all three. This long span includes a sequence motif that is also present in proteins of the myc, achaete-scute, and immunoglobulin enhancer-binding families. The herculin gene is physically linked to the Myf-5 gene on the chromosome; only 8.5 kilobases separate their translational start sites. A putative 27-kDa protein is encoded by three exons contained within a 1.7-kilobase fragment of the herculin gene. When expressed under the control of the simian virus 40 early promoter, transfected herculin renders murine NIH 3T3 and C3H/10T1/2 fibroblasts myogenic. In doing so, it also activates expression of myogenin, MyoD, and endogenous herculin in NIH 3T3 recipients. In adult mice, herculin is expressed in skeletal muscle but is absent from smooth muscle, cardiac muscle, and all nonmuscle tissues assayed. Direct comparison of the four known myogenic regulators in adult muscle showed that herculin is expressed at a significantly higher level than is any of the others. This quantitative dominance suggests an important role in the establishment or maintenance of adult skeletal muscle.


RAPID: Resource of Asian Primary Immunodeficiency Diseases.
Availability of a freely accessible, dynamic and integrated database for primary immunodeficiency diseases (PID) is important both for researchers as well as clinicians. To build a PID informational platform and also as a part of action to initiate a network of PID research in Asia, we have constructed a web-based compendium of molecular alterations in PID, named Resource of Asian Primary Immunodeficiency Diseases (RAPID), which is available as a worldwide web resource at http://rapid.rcai.riken.jp/. It hosts information on sequence variations and expression at the mRNA and protein levels of all genes reported to be involved in PID patients. The main objective of this database is to provide detailed information pertaining to genes and proteins involved in primary immunodeficiency diseases along with other relevant information about protein-protein interactions, mouse studies and microarray gene-expression profiles in various organs and cells of the immune system. RAPID also hosts a tool, mutation viewer, to predict deleterious and novel mutations and also to obtain mutation-based 3D structures for PID genes. Thus, information contained in this database should help physicians and other biomedical investigators to further investigate the role of these molecules in PID.


Superoxide production by phagocytic leukocytes.
Mononuclear phagocytic leukocytes, as well as polymorphonuclear leukocytes, produce and release superoxide at rest, and this is stimulated by phagocytosis. Of the mouse monocytic cells studied, alveolar macrophages released the largest amounts of superoxide during phagocytosis, followed by normal peritoneal macrophages. Casein-elicited and "activated" macrophages released smaller quantities. In the guinea pig, polymorphonuclear leukocytes and casein-elicited macrophages were shown to release superoxide during phagocytosis whereas alveolar macrophages did not. Superoxide release accounted for only a small fraction of the respiratory burst of phagocytosis in all but the normal mouse peritoneal macrophage, the guinea pig polymorphonuclear leukocyte, and probably the mouse alveolar macrophage. There are obviously considerable species differences in O2-release by various leukocytes that might reflect both the production and/or destruction (e.g. by dismutase) of that substance.


First Report of a Soft Rot of Phalaenopsis aphrodita Caused by Dickeya dieffenbachiae in China.
Phalaenopsis orchids, originally from tropical Asia, are mainly planted in Thailand, Singapore, Malaysia, the Philippines, and Taiwan and have gained popularity from consumers all over the world. The cultivation area of Phalaenopsis orchids has been rising and large-scale bases have been established in mainland China, especially South China because of suitable environmental conditions. In September 2011, a soft rot of Phalaenopsis aphrodita was found in a Phalaenopsis planting base in Guangzhou with an incidence of ~15%. Infected plants initially showed water-soaked, pale-to-dark brown pinpoint spots on leaves that were sometimes surrounded by a yellow halo. Spots expanded rapidly with rising humidity and temperatures, and in a few days, severely extended over the blade with a light tan color and darker brown border. Lesions decayed with odorous fumes and tissues collapsed with inclusions exuding. The bacterium advanced to the stem and pedicle. Finally, leaves became papery dry and the pedicles lodged. Six diseased samples were collected, and bacteria were isolated from the edge of symptomatic tissues after sterilization in 0.3% NaOCl for 10 min, rinsing in sterile water three times, and placing on nutrient agar for culture. Twelve representative isolates were selected for further characterization. All strains were gram negative, grew at 37°C, were positive for indole production, and utilized malonate, glucose, and sucrose but not glucopyranoside, trehalose, or palatinose. Biolog identification (version 4.20.05, Hayward, CA) was performed and Pectobacterium chrysanthemi (SIM 0.868) was confirmed for the tested isolates (transfer to genus Dickeya). PCR was used to amplify the 16S rDNAgene with primers 27f and 1492r, dnaX gene with primers dnaXf and dnaXr (3), and gyrB gene with primers gyrBf (5'-GAAGGYAAAVTKCATCGTCAGG-3') and gyrB-r1 (5'-TCARATATCRATATTCGCYGCTTTC-3') designed on the basis of the published gyrB gene sequences of genus Dickeya. BLASTn was performed online, and phylogeny trees (100% bootstrap values) were created by means of MEGA 5.05 for these gene sequences, respectively. Results commonly showed that the representative tested strain, PA1, was most homologous to Dickeya dieffenbachiae with 98% identity for 16S rDNA(JN940859), 97% for dnaX (JN989971), and 96% for gyrB (JN971031). Thus, we recommend calling this isolate D. dieffenbachiae PA1. Pathogenicity tests were conducted by injecting 10 P. aphrodita seedlings with 100 μl of the bacterial suspension (1 × 108 CFU/ml) and another 10 were injected with 100 μl of sterile water as controls. Plants were inoculated in a greenhouse at 28 to 32°C and 90% relative humidity. Soft rot symptoms were observed after 2 days on the inoculated plants, but not on the control ones. The bacterium was isolated from the lesions and demonstrated identity to the inoculated plant by the 16S rDNA sequence comparison. Previously, similar diseases of P. amabilis were reported in Tangshan, Jiangsu, Zhejiang, and Wuhan and causal agents were identified as Erwinia spp. (2), Pseudomonas grimontii (1), E. chrysanthemi, and E. carotovora subsp. carovora (4). To our knowledge, this is the first report of D. dieffenbachiae causing soft rot disease on P. aphrodita in China. References: (1) X. L. Chu and B. Yang. Acta Phytopathol. Sin. 40:90, 2010. (2) Y. M. Li et al. J. Beijing Agric. Coll. 19:41, 2004. (3) M. Sławiak et al. Eur. J. Plant Pathol. 125:245, 2009. (4) Z. Y. Wu et al. J. Zhejiang For. Coll. 27:635, 2010.


Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma.
Sixty-five patients with unresectable hilar cholangiocarcinoma (CCA) have undergone orthotopic liver transplantation (OLT) after neoadjuvant chemoradiotherapy per a clinical care protocol developed in 1993. We reviewed our experience with the aim to identify clinicopathological predictors of disease recurrence. All patients with CCA that underwent OLT at our institution between 1993 and January 1, 2006 were treated in accord with our published protocol. We analyzed multiple clinical and explant pathologic factors using Cox regression analysis. Sixty-five patients with CCA underwent OLT. Four patients died within six months due to postoperative complications. At last follow-up, 11 patients (17%) had developed recurrence seven to 64 months after OLT. Mean time to recurrence was 29 months, and eight patients had died from recurrent disease. Patient and disease-free survival were 76% and 60% five years after OLT. Predictors of recurrence were older age, pretransplant cancer antigen (CA) 19-9 >100 U/ml, prior cholecystectomy, mass on cross-sectional imaging, residual tumor in explant >2 cm, tumor grade and perineural invasion in explant. Underlying primary sclerosing cholangitis, percutaneous biliary intubation, gender, and other time points for CA 19-9 were not associated with recurrence. Prolonged staging-to-OLT intervals for patients transplanted after implementation of model for end-stage liver disease (MELD) showed a trend toward increased recurrence. Older patients and those with high CA-19.9 levels, and larger tumors are more likely to develop recurrent disease. Prolonged waiting time may emerge as a significant risk factor with longer follow-up. These findings may guide patient selection, applicability of live donor transplantation and MELD score exceptions for this aggressive protocol.


Contradictions in client-centred discharge planning: through the lens of relational autonomy.
While client-centred practice has received wide support, it remains difficult to apply in many practice settings. Identified barriers include constraints on time, resources, and services imposed by healthcare policies. Healthcare professionals' prioritizing of client safety over (other) interests that clients may name may further restrict the application of client-centred practice. Discharge planning is one area where such considerations can conflict. This paper presents a secondary analysis of data examining the process of discharge in one Canadian rehabilitation setting. It examines how discourses of client-centred practice and of prioritizing safety were reflected in discharge planning with older adults and considers the implications of potential conflicts between these discourses. Taking a critical bioethics perspective informed by relational autonomy theory, microethnographic case studies were used to examine discharge planning from the perspectives of older adult clients and healthcare professionals. Healthcare professionals interpreted client-centred practice to require abiding by client wishes, as long as this was safe; furthermore prioritizing safety took precedence over other considerations in discharge planning. Client-centred practice was not promoted in discharge planning processes in the research setting. Applying a relational autonomy lens to practice could promote approaches that better facilitate client-centred practice.


K-ras nanoclustering is subverted by overexpression of the scaffold protein galectin-3.
The spatial organization of K-Ras proteins into nanoclusters on the plasma membrane is essential for high-fidelity signal transduction. The mechanism underlying K-Ras nanoclustering is unknown. We show here that K-Ras.GTP recruits Galectin-3 (Gal-3) from the cytosol to the plasma membrane where it becomes an integral nanocluster component. Importantly, we show that the cytosolic level of Gal-3 determines the magnitude of K-Ras.GTP nanoclustering and signal output. The beta-sheet layers of the Gal-3 carbohydrate recognition domain contain a hydrophobic pocket that may accommodate the farnesyl group of K-Ras. V125A substitution within this hydrophobic pocket yields a dominant negative Gal-3(V125A) mutant that inhibits K-Ras activity. Gal-3(V125A) interaction with K-Ras.GTP reduces K-Ras.GTP nanocluster formation, which abrogates signal output from the Raf/mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK; MEK) pathway. Gal-3(V125A) negatively regulates cell growth and reduces cellular transformation. Thus, regulation of K-Ras nanocluster formation and signal output by Gal-3 critically depends on the integrity of the Gal-3 hydrophobic pocket. These results show that Gal-3 overexpression in breast cancer cells, which increases K-Ras signal output, represents oncogenic subversion of plasma membrane nanostructure.


Long-term effects of leucine-enkephalin on active avoidance responding in mice.
The effects of peripherally administered leucine-enkephalin on the acquisition and retention of active avoidance behavior was studied in mice. Mice received 4 training trials on Day 1, 24 test trials on Day 2, and 10 test trials on Day 5. Leucine-enkephalin impaired the aquisition of avoidance behavior when administered before testing on Day 2. Impairment of retention was demonstrated on Day 2 and Day 5 when leucine-enkephalin was administered immediately after training on Day 1, results indicating the long-term nature of the enkephalin effect. There was no effect of leucine-enkephalin when administered just prior to testing on Day 5. The impairing effect was attenuated but not blocked by naloxone. The pattern of the results from the different tests supports the hypothesis that leucine-enkephalin impairs both acquisition of learning and memory consolidation.


FOXQ1, a novel target of the Wnt pathway and a new marker for activation of Wnt signaling in solid tumors.
The forkhead box transcription factor FOXQ1 has been shown to be upregulated in colorectal cancer (CRC) and metastatic breast cancer and involved in tumor development, epithelial-mesenchymal transition and chemoresistance. Yet, its transcriptional regulation is still unknown. FOXQ1 mRNA and protein expression were analysed in a panel of CRC cell lines, and laser micro-dissected human biopsy samples by qRT-PCR, microarray GeneChip® U133 Plus 2.0 and western blots. FOXQ1 regulation was assayed by chromatin immunoprecipitation and luciferase reporter assays. FOXQ1 was robustly induced in CRC compared to other tumors, but had no predictive value with regards to grade, metastasis and survival in CRC. Prototype-based gene coexpression and gene set enrichment analysis showed a significant association between FOXQ1 and the Wnt pathway in tumors and cancer cell lines from different tissues. In vitro experiments confirmed, on a molecular level, FOXQ1 as a direct Wnt target. Analysis of known Wnt targets identified FOXQ1 as the most suitable marker for canonical Wnt activation across a wide panel of cell lines derived from different tissues. Our data show that FOXQ1 is one of the most over-expressed genes in CRC and a direct target of the canonical Wnt pathway. It is a potential new marker for detection of early CRC and Wnt activation in tumors of different origins.


Evaluation of dentoalveolar compensation in skeletal class II malocclusion in a Pakistani University Hospital setting.
To quantitatively evaluate the pattern of dentoalveolar compensation in skeletal class II patients and to find which dentoalveolar parameter compensates the most for this sagittal jaw discrepancy. Cross-sectional study. Dental Section, the Aga Khan University Hospital, Karachi, from January 2005 to March 2006. Cephalometric analyses were performed on pretreatment lateral cephalographs of 87 orthodontic patients who met the selection criteria. Various linear and angular measurements were taken. For a quantitative evaluation of dentoalveolar compensation, association was found between various dental and skeletal parameters by correlation analyses. To evaluate which parameter compensates the most, regression and scatters were performed keeping ANB angle as a measure of sagittal jaw discrepancy versus some parameters (SN-OP, A-NP, UI-NA, IIA, LI-OP, LI-SN, LI-FH, LI-MP). Statistically significant associations were seen between some skeletal and dental parameters. Correlation and regression analyses indicated SN-OP, LI-OP and LI-FH to be the most likely parameters to compensate for underlying sagittal jaw discrepancies. Lower incisor position and occlusal plane inclination in relation to the craniofacial structures are the most likely parameters for compensation in class II sagittal jaw discrepancy, evaluation of which may be helpful in treatment planning and treatment success.


The use of Amerindian charm plants in the Guianas.
Magical charm plants to ensure good luck in hunting, fishing, agriculture, love and warfare are known among many Amerindians groups in the Guianas. Documented by anthropologists as social and political markers and exchangeable commodities, these charms have received little attention by ethnobotanists, as they are surrounded by secrecy and are difficult to identify. We compared the use of charm species among indigenous groups in the Guianas to see whether similarity in charm species was related to geographical or cultural proximity. We hypothesized that cultivated plants were more widely shared than wild ones and that charms with underground bulbs were more widely used than those without such organs, as vegetatively propagated plants would facilitate transfer of charm knowledge. We compiled a list of charm plants from recent fieldwork and supplemented these with information from herbarium collections, historic and recent literature among 11 ethnic groups in the Guianas. To assess similarity in plant use among these groups, we performed a Detrended Component Analysis (DCA) on species level. To see whether cultivated plants or vegetatively propagated species were more widely shared among ethnic groups than wild species or plants without rhizomes, tubers or stem-rooting capacity, we used an independent sample t-test. We recorded 366 charms, representing 145 species. The majority were hunting charms, wild plants, propagated via underground bulbs and grown in villages. Our data suggest that similarity in charm species is associated with geographical proximity and not cultural relatedness. The most widely shared species, used by all Amerindian groups, is Caladium bicolor. The tubers of this plant facilitate easy transport and its natural variability allows for associations with a diversity of game animals. Human selection on shape, size and color of plants through clonal reproduction has ensured the continuity of morphological traits and their correlation with animal features. Charm plants serve as vehicles for traditional knowledge on animal behavior, tribal warfare and other aspects of oral history and should therefore deserve more scientific and societal attention, especially because there are indications that traditional knowledge on charms is disappearing.


Cytogenetic instability in ovarian epithelial cells from women at risk of ovarian cancer.
Fanconi anemia is an inherited cancer predisposition disease characterized by cytogenetic and cellular hypersensitivity to cross-linking agents. Seeking evidence of Fanconi anemia protein dysfunction in women at risk of ovarian cancer, we screened ovarian surface epithelial cells from 25 primary cultures established from 22 patients using cross-linker hypersensitivity assays. Samples were obtained from (a) women at high risk for ovarian cancer with histologically normal ovaries, (b) ovarian cancer patients, and (c) a control group with no family history of breast or ovarian cancer. In chromosomal breakage assays, all control cells were mitomycin C (MMC) resistant, but eight samples (five of the six high-risk and three of the eight ovarian cancer) were hypersensitive. Lymphocytes from all eight patients were MMC resistant. Only one of the eight patients had a BRCA1 germ-line mutation and none had BRCA2 mutations, but FANCD2 was reduced in five of the eight. Ectopic expression of normal FANCD2 cDNA increased FANCD2 protein and induced MMC resistance in both hypersensitive lines tested. No FANCD2 coding region or promoter mutations were found, and there was no genomic loss or promoter methylation in any Fanconi anemia genes. Therefore, in high-risk women with no BRCA1 or BRCA2 mutations, tissue-restricted hypersensitivity to cross-linking agents is a frequent finding, and chromosomal breakage responses to MMC may be a sensitive screening strategy because cytogenetic instability identified in this way antedates the onset of carcinoma. Inherited mutations that result in tissue-specific FANCD2 gene suppression may represent a cause of familial ovarian cancer.


The impact of disulfiram treatment on the reinforcing effects of cocaine: a randomized clinical trial.
Clinical trials indicate that disulfiram (250 mg/d) reduces cocaine use, though one study found that treatment with lower doses of disulfiram (62.5 and 125 mg/d) increased cocaine use. We conducted the present study to better understand how disulfiram alters the reinforcing effects of cocaine in cocaine users. Seventeen non-treatment seeking, cocaine-dependent volunteers participated in this double-blind, placebo-controlled, laboratory-based study. A cross-over design was utilized in which participants received placebo in one phase and disulfiram (250 mg/d) in the other. Following three days of study medication participants completed two choice sessions. In one they made 10 choices between receiving an intravenous infusion of saline or money that increased in value (US$ 0.05-16) and in the other cocaine (20 mg) or money. Participants chose cocaine more than saline under both disulfiram and placebo conditions (p<0.05). Unexpectedly, disulfiram increased both the number of cocaine and saline infusion choices (p<0.05). We next examined the relationship between disulfiram dose and cocaine choices. Disulfiram dose (mg/kg bodyweight) was negatively correlated with number of choices for cocaine (p<0.05). Disulfiram also enhanced cocaine-induced increases in cardiovascular measures (p's<0.05-0.01). Disulfiram's impact on the reinforcing effects of cocaine depends on dose relative to body weight. Our results suggest that the use of weight-based medication doses would produce more reliable effects, consistent with weight-based dosing used in pediatrics and in preclinical research. Clinicaltrials.gov NCT00729300.