BMP-2/ALK3 and HGF signal in parallel to regulate renal collecting duct morphogenesis.
Bone morphogenetic protein (BMP)-2 and hepatocyte growth factor (HGF) exert antagonistic effects on renal collecting duct formation during embryogenesis. A current model proposes HGF inhibits BMP-2 signaling at the level of Smad1 in a common target cell. Here, we show that BMP-2 and HGF control collecting duct formation via parallel pathways. We examined the interactions between BMP-2 and HGF in the mIMCD-3 model of collecting duct morphogenesis. During tubule formation, HGF rescued the inhibitory effects of BMP-2 and of a constitutive active form of the BMP-2 receptor, ALK3, stably expressed in mIMCD-3 cells. To determine whether the effect of HGF occurs through known mediators which act downstream of the BMP-2/ALK3 complex, we examined the effect of HGF on BMP-2-induced Smad1 phosphorylation, Smad1/Smad4 complex formation, and Smad1 nuclear translocation. Neither HGF nor other receptor tyrosine kinase ligands (EGF, FGF-4) induced phosphorylation of endogenous Smad1 in mIMCD-3 cells or in Mv1Lu, MC3T3-E1 or P19 cells. Furthermore, none of these ligands blocked induction of the BMP-responsive promoter, Tlx2. Thus, HGF overcomes the inhibitory effects of BMP-2 on collecting duct morphogenesis without interrupting any of the known signaling events in the BMP-2 dependent Smad1 signaling pathway. We conclude that BMP-2/ALK3 and HGF function to control parallel pathways downstream of their respective cell surface receptors. Integration of these signals likely occurs at the level of transcriptional or post-transcriptional events.


The fusion peptide of Semliki Forest virus associates with sterol-rich membrane domains.
Semliki Forest virus (SFV) is an enveloped alphavirus whose membrane fusion is triggered by low pH and promoted by cholesterol and sphingolipid in the target membrane. Fusion is mediated by E1, a viral membrane protein containing the putative fusion peptide. Virus mutant studies indicate that SFV's cholesterol dependence is controlled by regions of E1 outside of the fusion peptide. Both E1 and E1*, a soluble ectodomain form of E1, interact with membranes in a reaction dependent on low pH, cholesterol, and sphingolipid and form highly stable homotrimers. Here we have used detergent extraction and gradient floatation experiments to demonstrate that E1* associated selectively with detergent-resistant membrane domains (DRMs or rafts). In contrast, reconstituted full-length E1 protein or influenza virus fusion peptide was not associated with DRMs. Methyl beta-cyclodextrin quantitatively extracted both cholesterol and E1* from membranes in the absence of detergent, suggesting a strong association of E1* with sterol. Monoclonal antibody studies demonstrated that raft association was mediated by the proposed E1 fusion peptide. Thus, although other regions of E1 are implicated in the control of virus cholesterol dependence, once the SFV fusion peptide inserts in the target membrane it has a high affinity for membrane domains enriched in cholesterol and sphingolipid.


Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: a frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial.
Human colonic cancer is associated with multiple genetic deletions, mutations, and alterations in gene expression; in contrast, gene amplification has not been recognized as a prominent characteristic of human colonic tumors. Although the c-myc gene is overexpressed in approximately 70% of human colonic cancers, previous studies have not detected frequent gene amplification or rearrangement of c-myc in these tumors, although such amplification has been reported in chemically induced rodent colon cancer and quantitative analysis of gene copy number has shown the gene to be amplified at a low level in mucinous and poorly differentiated human colon carcinomas. Using rigorously controlled blot methodology, we have established that the c-myc gene, located at 8q21, exhibited amplification of 87% to 35-fold in 7 of 10 human colonic carcinoma cell lines. This was highly significant even at a low level of amplification in HT29 cells (P < 0.0001). Cytogenetic analysis by G-banding did not detect aneuploidy involving chromsome 8q, suggesting that the amplification for the c-myc gene on 8q was relatively specific, and this was consistent with a lack of amplification detected for the c-mos gene on 8q24, which was assayed similarly. The same methodology then revealed amplification of c-myc from 1.5-fold to 5-fold in 32% of tumors from 149 patients entered into a multi-institutional Phase III study of adjuvant therapy for colon cancer. c-myc status was not related to time to recurrence or death, but low levels of c-myc amplification identified a subset of patients who showed a statistically significant increase in disease-free survival, and a corresponding trend to longer overall survival, in response to adjuvant therapy with 5-fluorouracil plus levamisole. Presence of c-myc amplification was not related to incidence of p53 mutations.


Intralesional bleomycin for warts: a review.
Intralesional bleomycin has been used for the treatment of warts since the 1970s. Currently, there is a limited amount of evidence from randomized placebo-controlled trials comparing intralesional bleomycin with other local treatments for warts. Numerous reports have been published on the use of intralesional bleomycin for the treatment of recalcitrant warts with cure rates ranging from 14% to 99%. The majority of the data suggests that bleomycin is effective in over two-thirds of the reported cases with minimal side effects. In this paper, we review the mechanism of action, pharmacokinetics, safety profile, supply and storage, dosage scheme, techniques for administration, and efficacy of intralesional bleomycin for the treatment of warts.


Men's and women's pathways to adulthood and associated substance misuse.
Social role transitions have been linked to changes in substance use and misuse during young adulthood. This study examined how commonly observed pathways to adulthood, defined by education, employment, marriage, and parenthood, were associated with alcohol, tobacco, and marijuana misuse from ages 18 to 33. Data came from a longitudinal panel of 412 men and 396 women recruited when they were in fifth grade in Seattle public schools in 1985. Participants were followed through age 33 in 2008, with 92% retention. Young adults who had little postsecondary education and remained unmarried through age 30 generally had the highest rates of substance misuse. Those who were involved in postsecondary education and postponed family formation had the lowest rates, particularly with respect to daily smoking and nicotine dependence. Parenting during the young adult years was associated with lower rates of substance misuse for both men and women. However, taking on parenting responsibilities early, during the late teen years and early 20s (observed mostly for women), was associated with higher rates of tobacco misuse. Differences in substance misuse by pathways to adulthood were fairly constant across the young adulthood years and were already observed at age 18, suggesting that substance misuse patterns are established early. Young adults may change their substance use only partially in response to new freedoms and responsibilities in young adulthood. Preventive efforts should include a focus on early initiation of substance use and educational experiences that move people into life trajectories and associated substance misuse patterns.


SBpipe: a collection of pipelines for automating repetitive simulation and analysis tasks.
The rapid growth of the number of mathematical models in Systems Biology fostered the development of many tools to simulate and analyse them. The reliability and precision of these tasks often depend on multiple repetitions and they can be optimised if executed as pipelines. In addition, new formal analyses can be performed on these repeat sequences, revealing important insights about the accuracy of model predictions. Here we introduce SBpipe, an open source software tool for automating repetitive tasks in model building and simulation. Using basic YAML configuration files, SBpipe builds a sequence of repeated model simulations or parameter estimations, performs analyses from this generated sequence, and finally generates a LaTeX/PDF report. The parameter estimation pipeline offers analyses of parameter profile likelihood and parameter correlation using samples from the computed estimates. Specific pipelines for scanning of one or two model parameters at the same time are also provided. Pipelines can run on multicore computers, Sun Grid Engine (SGE), or Load Sharing Facility (LSF) clusters, speeding up the processes of model building and simulation. SBpipe can execute models implemented in COPASI, Python or coded in any other programming language using Python as a wrapper module. Future support for other software simulators can be dynamically added without affecting the current implementation. SBpipe allows users to automatically repeat the tasks of model simulation and parameter estimation, and extract robustness information from these repeat sequences in a solid and consistent manner, facilitating model development and analysis. The source code and documentation of this project are freely available at the web site: https://pdp10.github.io/sbpipe/ .


Counting quality because quality counts: differing standards in master's in medical education programmes.
In the United Kingdom the medical teacher role is being formalized. One result is that Masters level programmes in medical education are proliferating; however little or no attempt has been made to capture any differences in quality offered by them. A small scale project (Allery et al. 2006) set out to rectify this omission. Drawing on data from that study, this paper considers the variation in standards across programmes. Specifically research methods training provided in MMEd courses and levels of support for researchers is investigated. A secondary analysis of the data generated by the evaluative study and gathered via review of programme web sites, semi structured interviews with MSc course directors and case studies in two sites, identified from purposive sampling. Variations in both taught and research elements were identified. The quality of the research experience was compromised for some students many of whom were poorly prepared to undertake educational research and the question of standards raised in respect of those institutions where the examination process lacked real academic rigour. The variance in research methods training and support raises a number of issues in relation to quality standards. The medical education community needs to engage in open and critical dialogue around the whole constellation of paradigms, methods and activities that pertain in educational research. Unless or until we address these deeper concerns, research into medical education will suffer through a lack of design flair, implementation and rigour.


Mendelian randomisation analysis provides no evidence for a relationship between adult height and testicular cancer risk.
Observational studies have suggested anthropometric traits, particularly increased height are associated with an elevated risk of testicular cancer (testicular germ cell tumour). However, there is an inconsistency between study findings, suggesting the possibility of the influence of confounding factors. To examine the association between anthropometric traits and testicular germ cell tumour using an unbiased approach, we performed a Mendelian randomisation study. We used genotype data from genome wide association studies of testicular germ cell tumour totalling 5518 cases and 19,055 controls. Externally weighted polygenic risk scores were created and used to evaluate associations with testicular germ cell tumour risk per one standard deviation (s.d) increase in genetically-defined adult height, adult BMI, adult waist hip ratio adjusted for BMI (WHRadjBMI), adult hip circumference adjusted for BMI (HIPadjBMI), adult waist circumference adjusted for BMI (WCadjBMI), birth weight (BW) and childhood obesity. Mendelian randomisation analysis did not demonstrate an association between any anthropometric trait and testicular germ cell tumour risk. In particular, despite good power, there was no global evidence for association between height and testicular germ cell tumour. However, three SNPs for adult height individually showed association with testicular germ cell tumour (rs4624820: OR = 1.47, 95% CI: 1.41-1.55, p = 2.7 × 10-57 ; rs12228415: OR = 1.17, 95% CI: 1.11-1.22, p = 3.1 × 10-10 ; rs7568069: OR = 1.13, 95% CI: 1.07-1.18, p = 1.1 × 10-6 ). This Mendelian randomisation analysis, based on the largest testicular germ cell tumour genome wide association dataset to date, does not support a causal etiological association between anthropometric traits and testicular germ cell tumour aetiology. Our findings are more compatible with confounding by shared environmental factors, possibly related to prenatal growth with exposure to these risk factors occurring in utero.


Characterization of the metabolites of the peptidomimetic human immunodeficiency virus type 1 protease inhibitor SK&F 107461 in rats using liquid chromatography/mass spectrometry.
The metabolic fate of SK&F 107461 [Cbz-Ala-Ala-Phe psi [CHOHCH2] Gly-Val-Val-OMe], a potent and specific inhibitor of the protease encoded by human immunodeficiency virus type 1, in male Sprague-Dawley rats is described. SK&F 107461 is a hexapeptide analog containing a hydroxyethylene linkage in place of one of the peptide bonds, and in which the amino terminus is blocked with a carbobenzyloxy group and the carboxy terminus is modified to a methyl ester. The major metabolites of SK&F 107461 found in bile and urine after intravenous administration of 3H-labeled compound were characterized by LC/MS using either thermospray or continuous flow/FAB models of ionization. Approximately 80% of the administered radioactivity was recovered in the bile of bile duct-exteriorized rats following an intravenous dose. Radiochromatographic profiling indicated that SK&F 107461 was subject to extensive biotransformation. Structures were determined for three major biliary and five major urinary metabolites. Two of the major circulating plasma metabolites observed after intravenous bolus administration had similar retention times to metabolites that were observed in both bile and urine. A pathway for the biotransformation of SK&F 107461 in the rat is proposed. The parent molecule underwent two primary modes of metabolism. Hydrolysis of the carboxy-terminal ester or hydrolysis of the Ala-Ala peptide bond near the amino terminus were the primary metabolic events. All of the other metabolites characterized can be accounted for by exopeptidase activity subsequent to one or both of these primary events. There were no major metabolites observed resulting from anything other than hydrolysis of the ester or peptide bonds in the parent molecule.


Modeling and numerical simulation of biotin carboxylase kinetics: implications for half-sites reactivity.
Biotin carboxylase catalyzes the ATP-dependent carboxylation of biotin and is one component of the multienzyme complex acetyl-CoA carboxylase that catalyzes the first committed step in fatty acid synthesis in all organisms. In Escherichia coli, biotin carboxylase exists as a homodimer where each subunit contains a complete active site. In a previous study (Janiyani, K., Bordelon, T., Waldrop, G.L., Cronan Jr., J.E., 2001. J. Biol. Chem. 276, 29864-29870), hybrid dimers were constructed where one subunit was wild-type and the other contained an active site mutation that reduced activity at least 100-fold. The activity of the hybrid dimers was only slightly greater than the activity of the mutant homodimers and far less than the expected 50% activity for completely independent active sites. Thus, there is communication between the two subunits of biotin carboxylase. The dominant negative effect of the mutations on the wild-type active site was interpreted as alternating catalytic cycles of the active sites in the homodimer. In order to test the hypothesis of oscillating catalytic cycles, mathematical modeling and numerical simulations of the kinetics of wild-type, hybrid dimers, and mutant homodimers of biotin carboxylase were performed. Numerical simulations of biotin carboxylase kinetics were the most similar to the experimental data when an oscillating active site model was used. In contrast, alternative models where the active sites were independent did not agree with the experimental data. Thus, the numerical simulations of the proposed kinetic model support the hypothesis that the two active sites of biotin carboxylase alternate their catalytic cycles.


Low numbers of ovarian follicles ≥3 mm in diameter are associated with low fertility in dairy cows.
The total number of ovarian follicles ≥ 3mm in diameter (antral follicle count, AFC) during follicular waves varies among cattle of similar age, but AFC is highly repeatable within individuals. We hypothesized that lower AFC could be associated with reduced fertility in cattle. The AFC was assessed by ultrasonography for 2 d consecutively during the first wave of follicular growth of the estrous cycle, 4.6±1.43 d (mean ± SD) after estrus, in 306 Holstein-Friesian dairy cows approximately 70 d postpartum. Cows were classified into 3 groups based on AFC: low (AFC ≤15), intermediate (AFC=16 to 24), and high (AFC ≥25). During the cycle in which AFC was assessed and in subsequent cycles, cows were artificially inseminated (AI) following detection of estrus, and pregnancy status was assessed using ultrasonography. Cows with high AFC had 3.34 times greater odds of being pregnant at the end of the breeding season compared with cows with low AFC; the odds of a successful pregnancy at first service were 1.75 times greater in the intermediate compared with the low group. The predicted probability of a successful pregnancy by the end of the breeding period (length of breeding season was 86±16.3 d) was 94, 88, and 84% for the high, intermediate, and low AFC groups, respectively. No difference was evident among groups in 21-d submission rate (proportion of all cows detected in estrus and submitted for AI in the first 21 d of the breeding season), but the interval from calving to conception was shorter in the high (109.5±5.1 d) versus low (117.1±4 d) group, and animals with intermediate AFC received fewer services during the breeding season (2.3±0.1) compared with animals with low AFC (2.7±0.1). Lactating cows with ≤15 ovarian follicles have lower reproductive performance compared with cows with higher numbers of follicles, but the existence of a positive association between high numbers of ovarian follicles and fertility is yet to be established.


Characterization of CD4+ T-cell-dendritic cell interactions during secondary antigen exposure in tolerance and priming.
Despite the recent advances in our understanding of the dynamics of the cellular interactions associated with the induction of immune responses, comparatively little is known about the in vivo behaviour of antigen-experienced T cells upon secondary antigen exposure in either priming or tolerance. Such information would provide an insight into the functional mechanisms employed by memory T cells of distinct phenotypes and provide invaluable knowledge of how a specific tolerogenic or immunogenic state is maintained. Using real-time imaging to follow the in vivo motility of naïve, primed and tolerized CD4(+) T cells and their interactions with dendritic cells (DCs), we demonstrate that each of these distinct functional phenotypes is associated with specific patterns of behaviour. We show that antigen-experienced CD4(+) T cells, whether primed or tolerized, display inherently slower migration, making many short contacts with DCs in the absence of antigen. Following secondary exposure to antigen, primed T cells increase their intensity or area of interaction with DCs whereas contacts between DCs and tolerized T cells are reduced. Importantly, this was not associated with alterations in the contact time between DCs and T cells, suggesting that T cells that have previously encountered antigen are more effective at surveying DCs. Thus, our studies are the first to demonstrate that naïve, primed and tolerized T cells show distinct behaviours before and after secondary antigen-encounter, providing a novel mechanism for the increased immune surveillance associated with memory T cells. These findings have important consequences for many immunotherapeutics, which aim to manipulate secondary immune responses.


Microstructure and optical properties of Pr3+-doped hafnium silicate films.
In this study, we report on the evolution of the microstructure and photoluminescence properties of Pr3+-doped hafnium silicate thin films as a function of annealing temperature (TA). The composition and microstructure of the films were characterized by means of Rutherford backscattering spectrometry, spectroscopic ellipsometry, Fourier transform infrared absorption, and X-ray diffraction, while the emission properties have been studied by means of photoluminescence (PL) and PL excitation (PLE) spectroscopies. It was observed that a post-annealing treatment favors the phase separation in hafnium silicate matrix being more evident at 950°C. The HfO2 phase demonstrates a pronounced crystallization in tetragonal phase upon 950°C annealing. Pr3+ emission appeared at TA = 950°C, and the highest efficiency of Pr3+ ion emission was detected upon a thermal treatment at 1,000°C. Analysis of the PLE spectra reveals an efficient energy transfer from matrix defects towards Pr3+ ions. It is considered that oxygen vacancies act as effective Pr3+ sensitizer. Finally, a PL study of undoped HfO2 and HfSiOx matrices is performed to evidence the energy transfer.


SplicerEX: a tool for the automated detection and classification of mRNA changes from conventional and splice-sensitive microarray expression data.
The key postulate that one gene encodes one protein has been overhauled with the discovery that one gene can generate multiple RNA transcripts through alternative mRNA processing. In this study, we describe SplicerEX, a novel and uniquely motivated algorithm designed for experimental biologists that (1) detects widespread changes in mRNA isoforms from both conventional and splice sensitive microarray data, (2) automatically categorizes mechanistic changes in mRNA processing, and (3) mitigates known technological artifacts of exon array-based detection of alternative splicing resulting from 5' and 3' signal attenuation, background detection limits, and saturation of probe set signal intensity. In this study, we used SplicerEX to compare conventional and exon-based Affymetrix microarray data in a model of EBV transformation of primary human B cells. We demonstrated superior detection of 3'-located changes in mRNA processing by the Affymetrix U133 GeneChip relative to the Human Exon Array. SplicerEX-identified exon-level changes in the EBV infection model were confirmed by RT-PCR and revealed a novel set of EBV-regulated mRNA isoform changes in caspases 6, 7, and 8. Finally, SplicerEX as compared with MiDAS analysis of publicly available microarray data provided more efficiently categorized mRNA isoform changes with a significantly higher proportion of hits supported by previously annotated alternative processing events. Therefore, SplicerEX provides an important tool for the biologist interested in studying changes in mRNA isoform usage from conventional or splice-sensitive microarray platforms, especially considering the expansive amount of archival microarray data generated over the past decade. SplicerEX is freely available upon request.


A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2.
A single missense mutation was identified in a novel, highly conserved zinc-finger gene, ZCD2, in three consanguineous families of Jordanian descent with Wolfram syndrome (WFS). It had been shown that these families did not have mutations in the WFS1 gene (WFS1) but were mapped to the WFS2 locus at 4q22-25. A G-->C transversion at nucleotide 109 predicts an amino acid change from glutamic acid to glutamine (E37Q). Although the amino acid is conserved and the mutation is nonsynonymous, the pathogenesis for the disorder is because the mutation also causes aberrant splicing. The mutation was found to disrupt messenger RNA splicing by eliminating exon 2, and it results in the introduction of a premature stop codon. Mutations in WFS1 have also been found to cause low-frequency nonsyndromic hearing loss, progressive hearing loss, and isolated optic atrophy associated with hearing loss. Screening of 377 probands with hearing loss did not identify mutations in the WFS2 gene. The WFS1-encoded protein, Wolframin, is known to localize to the endoplasmic reticulum and plays a role in calcium homeostasis. The ZCD2-encoded protein, ERIS (endoplasmic reticulum intermembrane small protein), is also shown to localize to the endoplasmic reticulum but does not interact directly with Wolframin. Lymphoblastoid cells from affected individuals show a significantly greater rise in intracellular calcium when stimulated with thapsigargin, compared with controls, although no difference was observed in resting concentrations of intracellular calcium.


Managing player load in professional rugby union: a review of current knowledge and practices.
The loads to which professional rugby players are subjected has been identified as a concern by coaches, players and administrators. In November 2014, World Rugby commissioned an expert group to identify the physical demands and non-physical load issues associated with participation in professional rugby. To describe the current state of knowledge about the loads encountered by professional rugby players and the implications for their physical and mental health. The group defined 'load' as it relates to professional rugby players as the total stressors and demands applied to the players. In the 2013-2014 seasons, 40% of professional players appeared in 20 matches or more, and 5% of players appeared in 30 matches or more. Matches account for ∼5-11% of exposure to rugby-related activities (matches, team and individual training sessions) during professional competitions. The match injury rate is about 27 times higher than that in training. The working group surmised that players entering a new level of play, players with unresolved previous injuries, players who are relatively older and players who are subjected to rapid increases in load are probably at increased risk of injury. A mix of 'objective' and 'subjective' measures in conjunction with effective communication among team staff and between staff and players was held to be the best approach to monitoring and managing player loads. While comprehensive monitoring holds promise for individually addressing player loads, it brings with it ethical and legal responsibilities that rugby organisations need to address to ensure that players' personal information is adequately protected. Administrators, broadcasters, team owners, team staff and the players themselves have important roles in balancing the desire to have the 'best players' on the field with the ongoing health of players. In contrast, the coaching, fitness and medical staff exert significant control over the activities, duration and intensity of training sessions. If load is a major risk factor for injury, then managing training loads should be an important element in enabling players to perform in a fit state as often as possible.


Depolarization-activated potentiation of the T fiber synapse in the blue crab.
The blue crab T fiber synapse, associated with the stretch receptor of the swimming leg, has a nonspiking presynaptic element that mediates tonic transmission. This synapse was isolated and a voltage clamp circuit was used to control the membrane potential at the release sites. The dependence of transmitter release on extracellular calcium, [Ca]o, was studied over a range of 2.5-40 mM. A power relationship of 2.7 was obtained between excitatory postsynaptic potential (EPSP) rate of rise and [Ca]o. Brief presynaptic depolarizing steps, 5-10 ms, presented at 0.5 Hz activated EPSP's of constant amplitude. Inserting a 300-ms pulse (conditioning pulse) between these test pulses potentiated the subsequent test EPSPs. This depolarization-activated potentiation (DAP) lasted for 10-20 s and decayed with a single exponential time course. The decay time course remained invariant with test pulse frequencies ranging from 0.11 to 1.1 Hz. The magnitude and decay time course of DAP were independent of the test pulse amplitudes. The magnitude of DAP was a function of conditioning pulse amplitudes. Large conditioning pulses activated large potentiations, whereas the decay time constants were not changed. The DAP is a Ca-dependent process. When the amplitude of conditioning pulses approached the Ca equilibrium potential, the magnitude of potentiation decreased. Repeated application of conditioning pulses, at 2-s intervals, did not produce additional potentiation beyond the level activated by the first conditioning pulse. Comparison of the conditioning EPSP waveforms activated repetitively indicated that potentiation lasted transiently, 100 ms, during a prolonged release. Possible mechanisms of the potentiation are discussed in light of these new findings.


Drivers of species turnover vary with species commonness for native and alien plants with different residence times.
Communities comprising alien species with different residence times are natural experiments allowing the assessment of drivers of community assembly over time. Stochastic processes (such as dispersal and fluctuating environments) should be the dominant factors structuring communities of exotic species with short residence times. In contrast, communities should become more similar, or systematically diverge, if they contain exotics with increasing resident times, due to the increasing importance of deterministic processes (such as environmental filtering). We use zeta diversity (the number of species shared by multiple assemblages) to explore the relationship between the turnover of native species and two categories of alien species with different residence times (archaeophytes [introduced between 4000 BC and 1500 AD] and neophytes [introduced after 1500 AD]) in a network of nature reserves in central Europe. By considering multiple assemblages simultaneously, zeta diversity allows us to determine the contribution of rare and widespread species to turnover. Specifically, we explore the relative effects of assembly processes representing isolation by distance, environmental filtering, and environmental stochasticity (fluctuating environments) on zeta diversity using Multi-Site Generalized Dissimilarity Modelling (MS-GDM). Four clusters of results emerged. First, stochastic processes for structuring plant assemblages decreased in importance with increasing residence time. Environmental stochasticity only affected species composition for neophytes, offering possibilities to predict the spread debt of recent invasions. Second, native species turnover was well explained by environmental filtering and isolation by distance, although these factors did not explain the turnover of archaeophytes and neophytes. Third, native and alien species compositions were only correlated for rare species, whereas turnover in widespread alien species was surprisingly unrelated to the composition of widespread native species. Site-specific approaches would therefore be more appropriate for the monitoring and management of rare alien species, whereas species-specific approaches would suit widespread species. Finally, the size difference of nature reserves influences not only native species richness, but also their richness-independent turnover. A network of reserves must therefore be designed and managed using a variety of approaches to enhance native diversity, while controlling alien species with different residence times and degrees of commonness.


Synthetic approaches towards structurally-defined electrochemically and (photo)redox-active polymer architectures.
Electrochemically active polymers are widely used in (opto)electronic applications, e.g. organic light-emitting diodes (OLEDs), organic field-effect transistors (OFETs), solar cells or other light harvesting devices. In this regard, the progress in controlled polymerization techniques opens new possibilities to construct covalently linked polymer architectures, e.g. block copolymers or graft copolymers, from defined building blocks. These architectures represent promising candidates for application in (opto)electronic devices as they allow control of the morphology through self-assembly processes and, furthermore, are capable of mimicking fundamental processes for directional charge transport or light harvesting. This review details synthetic approaches to prepare functional redox-active and conjugated homopolymers as well as the construction of covalently linked well-defined architectures thereof, e.g. block copolymers, graft copolymers or chain end functionalized assemblies.


HOCOMOCO: expansion and enhancement of the collection of transcription factor binding sites models.
Models of transcription factor (TF) binding sites provide a basis for a wide spectrum of studies in regulatory genomics, from reconstruction of regulatory networks to functional annotation of transcripts and sequence variants. While TFs may recognize different sequence patterns in different conditions, it is pragmatic to have a single generic model for each particular TF as a baseline for practical applications. Here we present the expanded and enhanced version of HOCOMOCO (http://hocomoco.autosome.ru and http://www.cbrc.kaust.edu.sa/hocomoco10), the collection of models of DNA patterns, recognized by transcription factors. HOCOMOCO now provides position weight matrix (PWM) models for binding sites of 601 human TFs and, in addition, PWMs for 396 mouse TFs. Furthermore, we introduce the largest up to date collection of dinucleotide PWM models for 86 (52) human (mouse) TFs. The update is based on the analysis of massive ChIP-Seq and HT-SELEX datasets, with the validation of the resulting models on in vivo data. To facilitate a practical application, all HOCOMOCO models are linked to gene and protein databases (Entrez Gene, HGNC, UniProt) and accompanied by precomputed score thresholds. Finally, we provide command-line tools for PWM and diPWM threshold estimation and motif finding in nucleotide sequences.


Association of early imaging for back pain with clinical outcomes in older adults.
In contrast to the recommendations for younger adults, many guidelines allow for older adults with back pain to undergo imaging without waiting 4 to 6 weeks. However, early imaging may precipitate interventions that do not improve outcomes. To compare function and pain at the 12-month follow-up visit among older adults who received early imaging with those who did not receive early imaging after a new primary care visit for back pain without radiculopathy. Prospective cohort of 5239 patients 65 years or older with a new primary care visit for back pain (2011-2013) in 3 US health care systems. We matched controls 1:1 using propensity score matching of demographic and clinical characteristics, including diagnosis, pain severity, pain duration, functional status, and prior resource use. Diagnostic imaging (plain films, computed tomography [CT], magnetic resonance imaging [MRI]) of the lumbar or thoracic spine within 6 weeks of the index visit. back or leg pain-related disability measured by the modified Roland-Morris Disability Questionnaire (score range, 0-24; higher scores indicate greater disability) 12 months after enrollment. Among the 5239 patients, 1174 had early radiographs and 349 had early MRI/CT. At 12 months, neither the early radiograph group nor the early MRI/CT group differed significantly from controls on the disability questionnaire. The mean score for patients who underwent early radiography was 8.54 vs 8.74 among the control group (difference, -0.10 [95% CI, -0.71 to 0.50]; mixed model, P = .36). The mean score for the early MRI/CT group was 9.81 vs 10.50 for the control group (difference,-0.51 [-1.62 to 0.60]; mixed model, P = .18). Among older adults with a new primary care visit for back pain, early imaging was not associated with better 1-year outcomes. The value of early diagnostic imaging in older adults for back pain without radiculopathy is uncertain.


Comparison of outcomes of illicit drug users and nonusers hospitalized with heart failure.
The long-term effects of illicit drug use (IDU) on the clinical outcome of patients with heart failure (HF) are not well described. The objective of the present study was to describe the characteristics of patients with HF who used illicit drugs and to determine the effects of IDU on the clinical outcomes such as in-hospital mortality and hospital readmission for HF. A retrospective cohort study was conducted that included all patients admitted with HF from June 2003 to September 2004 and followed up until 2008 at a university hospital serving an at-risk population. The patients were divided into 2 groups: IDU and non-IDU according to self-reported use or positive laboratory results. The outcome measures were in-hospital mortality, HF readmission rate, interval to readmission for HF, and average brain natriuretic peptide and troponin levels throughout the follow-up period. Of 646 reviewed records, 542, representing 357 patients, were included in the present analysis. Of the 357 patients, 53 patients were in the IDU group and 304 were in the non-IDU group. Kaplan-Meier log-rank analysis and Cox proportional hazard analysis showed that IDU was associated with a shorter interval to readmission for HF (hazard ratio 3.8, 95% confidence interval 2.3 to 10.7, p <0.0001) but not with in-hospital mortality (hazard ratio 0.7, 95% confidence interval 0.3 to 1.7, p = 0.4). Multiple linear regression analysis identified IDU as an independent variable for the HF readmission rate (p = 0.0001) but not for average brain natriuretic peptide or average troponin levels. In conclusion, the results of the present study have demonstrated that IDU was associated with a decreased interval to readmission for HF and greater HF readmission rates.


Covalent-reaction-induced interfacial assembly to transform doxorubicin into nanophotomedicine with highly enhanced anticancer efficiency.
Herein, we show that a molecular assembly offers tremendous opportunities of affording existing building units with new physicochemical properties, holding promise in wide applications. Herein, we develop a facile covalent assembly using a natural occurring linker, genipin, to efficiently transform a traditional chemo drug, doxorubicin, into a nanophotomedicine. A possible mechanism is proposed, in which doxorubicin reacts with genipin through covalent bonding to produce poorly soluble units, which further form nuclei and mediate the interfacial assembly to generate uniform nanoparticles. Such assembled nanophotomedicine shows remarkably enhanced singlet oxygen generation ability (about 1000 folds), leading to a much higher photodynamic activity. Moreover, this self-carried nanodrug exhibits adjustable size, excellent colloidal stability, high capacity and preferable endocytosis. These favorable features lead to greatly improved anticancer efficiency under light at the same dosage, compared to that of pure doxorubin. We believe this study brings a new dimension to develop advanced drug delivery systems by molecular assembly.


Race- and Sex-Based Disparities in the Therapy and Outcomes of Squamous Cell Carcinoma of the Anus.
Background: Squamous cell carcinoma of the anus (SCCA) is one of the few cancers with an increasing incidence in the United States. We aimed to characterize race- and sex-based disparities in receipt of therapy and overall survival (OS) of SCCA using the SEER database. Methods: Cases of locoregional SCCA (T2-T4 any N M0) diagnosed between 2000 and 2012 in the SEER database were included. Demographics, tumor characteristics, type of therapy, and outcomes were extracted. Univariable and multivariable Cox proportional hazard models were constructed to test factors associated with OS. Data were reported as hazard ratios (HRs) and 95% CIs. Results: A total of 7,882 cases of locoregional SCCA were identified, with a median age of 58 years, 61.2% of whom were women, and 86.3% were white. Most patients (82.3%) received radiation therapy (RT), with the lowest rate in black men (76.7%) and the highest in white women (86.1%). The median OS was 135 months; OS was lower in elderly patients (age ≥65 years; 68 months), men (108 months), blacks (109 months), and those who did not receive RT (121 months). In multivariable analysis, age (HR, 1.19; 95% CI, 1.17-1.21 per 5 years increase), sex (HR, 1.59; 95% CI, 1.47-1.73, men vs women), race (HR, 1.51; 95% CI, 1.34-1.71, black vs white), and RT (HR, 0.90; 95% CI, 0.82-0.99) were independently associated with OS (P<.05). Conclusions: Significant race- and sex-based disparities exist in survival of patients with locoregional SCCA. Further investigation into the causes of these disparities and methods for elimination are warranted.


Development, inter-rater reliability and feasibility of a checklist to assess implementation (Ch-IMP) in systematic reviews: the case of provider-based prevention and treatment programs targeting children and youth.
Several papers report deficiencies in the reporting of information about the implementation of interventions in clinical trials. Information about implementation is also required in systematic reviews of complex interventions to facilitate the translation and uptake of evidence of provider-based prevention and treatment programs. To capture whether and how implementation is assessed within systematic effectiveness reviews, we developed a checklist for implementation (Ch-IMP) and piloted it in a cohort of reviews on provider-based prevention and treatment interventions for children and young people. This paper reports on the inter-rater reliability, feasibility and reasons for discrepant ratings. Checklist domains were informed by a framework for program theory; items within domains were generated from a literature review. The checklist was pilot-tested on a cohort of 27 effectiveness reviews targeting children and youth. Two raters independently extracted information on 47 items. Inter-rater reliability was evaluated using percentage agreement and unweighted kappa coefficients. Reasons for discrepant ratings were content analysed. Kappa coefficients ranged from 0.37 to 1.00 and were not influenced by one-sided bias. Most kappa values were classified as excellent (n = 20) or good (n = 17) with a few items categorised as fair (n = 7) or poor (n = 1). Prevalence-adjusted kappa coefficients indicate good or excellent agreement for all but one item. Four areas contributed to scoring discrepancies: 1) clarity or sufficiency of information provided in the review; 2) information missed in the review; 3) issues encountered with the tool; and 4) issues encountered at the review level. Use of the tool demands time investment and it requires adjustment to improve its feasibility for wider use. The case of provider-based prevention and treatment interventions showed relevancy in developing and piloting the Ch-IMP as a useful tool for assessing the extent to which systematic reviews assess the quality of implementation. The checklist could be used by authors and editors to improve the quality of systematic reviews, and shows promise as a pedagogical tool to facilitate the extraction and reporting of implementation characteristics.


Visor use among National Hockey League players and its relationship to on-ice performance.
To assess the use of half and three-quarter visors among National Hockey League (NHL) players and investigate the relationship between skill level and on-ice statistics such as points, penalty minutes and ice time and visor use. All players who played at least one game during the 2014-2015 NHL season were included in the study. Visor usage including three-quarter visor use was determined using official in-game images and video. Player information and statistics were obtained from a statistical hockey database. A multiple logistic regression model was used to study how the different player statistics influenced the probability of a player wearing a visor. Visor use was 87.1% among all NHL players (N=881) and 81.7% among all non-rookie players (N=612). Players who wore a visor were on average younger, played more games during the season, had more points, goals, assists and received more playing time. Players who did not wear a visor had 3 times more penalty minutes for every 100 min played. Only 11 (1.2%) players wore a three-quarter visor and these players were much older and contributed more to their team's offence when compared with the players who wore a one-half visor. Visor usage in the NHL continues to increase independent of new legislation making it mandatory for rookie players to wear a visor. Based on the results and the logistic regression model built in the study, those players who have the highest risk for not wearing a visor can be identified to help establish targeted interventions.


Spatial Distribution and Flight Patterns of Two Grain Storage Insect Pests, Rhyzopertha dominica (Bostrichidae) and Tribolium castaneum (Tenebrionidae): Implications for Pest Management.
The lesser grain borer, Rhyzopertha dominica, and the rust red flour beetle, Tribolium castaneum, are two major beetle pests commonly found infesting stored products worldwide. Both species can cause severe economic damage and their management is complicated by their potential to develop resistance to several of the limited chemical options available. However, pest management strategies can be improved by understanding the ecology of the pest insect. To determine the spatiotemporal activity of R. dominica and T. castaneum, we conducted a trapping study over two years in a temperate region of south-eastern Australia, with traps located near grain storages and fields. We captured higher numbers of R. dominica than T. castaneum, and both species were more prevalent in traps located close to grain storages. Similar and consistent seasonal patterns were displayed by both species with activity ceasing during the winter (June-August) months. We found linear correlations between maximum daily temperatures and trap catches, and minimum threshold temperatures for flight activity were 14.5 °C and 15.6 °C for R. dominica and T. castaneum, respectively. The results are discussed in relation to the ecology of these pests along with their implications for pest management.


Construction of an Exome-Wide Risk Score for Schizophrenia Based on a Weighted Burden Test.
Polygenic risk scores obtained as a weighted sum of associated variants can be used to explore association in additional data sets and to assign risk scores to individuals. The methods used to derive polygenic risk scores from common SNPs are not suitable for variants detected in whole exome sequencing studies. Rare variants, which may have major effects, are seen too infrequently to judge whether they are associated and may not be shared between training and test subjects. A method is proposed whereby variants are weighted according to their frequency, their annotations and the genes they affect. A weighted sum across all variants provides an individual risk score. Scores constructed in this way are used in a weighted burden test and are shown to be significantly different between schizophrenia cases and controls using a five-way cross-validation procedure. This approach represents a first attempt to summarise exome sequence variation into a summary risk score, which could be combined with risk scores from common variants and from environmental factors. It is hoped that the method could be developed further.


The Minimal Eating Observation Form-II (MEOF-II): cross-cultural validation of the Chinese version for people with stroke.
Eating difficulties are common among patients affected by stroke. A valid, reliable instrument for assessing eating difficulties in people with stroke is needed. The aim of this study was to translate the Minimal Eating Observation Form - version II (MEOF-II) for patients with stroke into Chinese and to comprehensively evaluate its reliability and validity. The scale of the original MEOF-II form was translated into Chinese using the cross-culture translation method, and 125 participants with stroke were assessed. Data were analysed by content validity index, Cronbach's alpha, correlations and exploratory factor analysis (EFA). Reliability and validity were demonstrated for the scale. A three-factor structure was illustrated by EFA, and construct validity was demonstrated by good convergent and discriminant validity. The Chinese version (Ch-MEOF-II) shows good reliability and validity in this study and can be applicable to assess eating difficulties in people with stroke; The Ch-MEOF-II allows the early recognition of eating difficulties and thus provides guidance of proper clinical interventions. For future study, a confirmatory factor analysis may need to confirm the three-factor structure identified in this study. Furthermore, a cross-cultural comparison can be conducted with the availability of the three different validated language versions of the MEOF-II form.


Experiences with implementation of evidence-based prevention programs to prevent occupational skin diseases in different occupations.
Occupational skin diseases are among the most frequently recognized occupational diseases in many industrialized countries. This paper describes and review experiences with implementation of interventions to prevent occupational skin diseases in different occupational settings representing the food processing industry and a hospital. The study populations were gut cleaners with all participants being exposed to wet work, cheese dairies and a hospital where all employees were included. The effect of implementation of evidence-based prevention programs were tested by questionnaire surveys on baseline and follow-up. A significant reduction in eczema at hands or forearms was observed among gut cleaners. At cheese dairies the eczema frequencies were low except for a comparison dairy where significant changes were seen. At the hospital a non significant reduction in hand eczema was observed. Changes related to use of protective measures and knowledge on prevention of occupational skin diseases were observed. A process evaluation carried out at the gut cleaning departments showed association between the eczema frequency at follow-up, activities related to prevention and implementation of an occupational health management system. In addition to documenting the scientific background for evidence-based prevention programs to prevent occupational skin diseases in different occupations, both the study population and the study design should be considered carefully when testing the implementation of workplace interventions. These aspects may influence the outcome in different directions and either facilitate or hamper the possibilities to provide scientific documentation of the effect of the intervention tested.


Characterization of Diarrheagenic Enteroaggregative Escherichia coli in Danish Adults-Antibiotic Treatment Does Not Reduce Duration of Diarrhea.
Enteroaggregative Escherichia coli (EAEC) is frequently isolated from sporadic cases of diarrhea and in outbreaks of gastroenteritis in several regions of the world. The pathophysiology of EAEC continues to be enigmatic, and the efficacy of antibiotic treatment in EAEC-associated diarrhea has been discussed. Since the level of antibiotic resistance is increasing, it is essential to restrict the use of antibiotics to prevent further resistance development. We aimed to investigate EAEC strains in adult Danish patients suffering from diarrhea and from healthy controls. We examined the antibiotic resistance in EAEC strains, the clinical response to antibiotic treatment in EAEC diarrheal cases, and the distribution of virulence genes in diarrheal cases. The EAEC strains were collected from patients suffering from diarrhea in a Danish multicenter study. A medical doctor interviewed the patients by using a questionnaire regarding gastrointestinal symptoms, exposures, and use of antibiotic and over-the-counter antidiarrheal drugs. Follow-up was performed after 3-5 months to inquire about differential diagnosis to gastrointestinal disease. A multiplex polymerase chain reaction characterized virulence genes in diarrheal cases. Finally, the level of antibiotic resistance was examined by using the disc diffusion method. Asymptomatic carriage of EAEC in the adult Danish population was rare, in contrast to findings in healthy Danish children. The duration of diarrhea was not shortened by antibiotic treatment, specifically ciprofloxacin treatment, or by over-the-counter antidiarrheal drugs. Follow-up revealed no pathology in diarrheal patients apart from irritable bowel syndrome in two patients. A high number of patients suffered from long-term diarrhea, which was associated with the enterotoxin EAST-1 and a high virulence factor score. A high level of antibiotic resistance was observed and 58% of the EAEC strains were multidrug resistant. Multidrug resistance was most pronounced in cases of travelers' diarrhea, and it was seen that antibiotic treatment did not reduce the duration of diarrhea.


The potential of RNA as a target for national screening of pre-cancer.
Whole national screening of pre-cancer is done only in some few countries, dominated by The Netherlands, Denmark, UK, Norway and Finland. These national screenings are done combining national cancer registry, national public health and national medical bodies or hospitals. Until some few years ago national screening was only done using morphological or visual methods or technology. Today a number of molecular methods have been implemented to serve these national screening programs. Based on all the discussions within this review, it is clear that the main driving engine and the cause of cervical pre-cancer and the main cause of invasive cervical cancer is the expression of E6 and E7 oncoproteins from HPV 16, 18, 31, 33 and 45. However, the main challenge is the role of morphology or imaging-based diagnosis in the original definition of pre-cancer disease. This definition is not based on the cause of cervical precancer but based on a complex, subjective, morphological observations. The difference between these two definitions are discussed in this review. The unique discovery done while validating the first standardized detection technology used against mRNA, confirmed that the presence of both abnormal E6 and/or E7 mRNA and protein is the cause of cervical pre-cancer or severe neoplasia and the main cause of invasive cervical cancer. This confirmation was evident even though all these studies were disturbed by the above defined biases from morphology or imaging-based diagnosis. The use of the screening target that cause stable and high expression of the most carcinogenic compounds ever discovered, must cause a more accurate screening program. A number of studies have proved that the detection of E6/E7 mRNA followed-up by indirect or direct treatment in a well-organized national screening program, would reduce the incidence of cervical cancer. This review discusses the main studies involved in the scientific, clinical evaluation and how this unique technology could be used as a new medical gold standard for national screening of cervical pre-cancer.


A null model of morphospace occupation.
Progress in understanding the relationship between lineage diversity, morphological diversity, and morphospace dynamics has been hampered by the lack of an appropriate null model of morphospace occupation. In this article, we introduce a simple class of models based on branching random walks (BRWs) for continuous traits. We show that many of the observed patterns of morphospace occupation might be simply a consequence of the dynamics of BRWs and therefore might not require special explanations. We also provide expected patterns of morphospace occupation according to a number of different conditions. In particular, we model BRWs on neutral landscapes and demonstrate that clumping in morphospace is possible even in the absence of adaptive landscapes with well-defined peaks and valleys. The quantitative definition of the BRW provides a means to analyze, both computationally and analytically, patterns of morphospace occupation according to different hypotheses.


Simultaneous alignment of dual-axis tilt series.
We present a strategy for the alignment of dual-axis tomographic series, based on reference points and simultaneous alignment of both series. Each series is first aligned individually, an affine transformation is determined to bring the two series in a unique reference system, and all experimental coordinates are combined in a single system of equations. In case of severe shrinkage, a global and a local refinement of the orientation parameters are performed to correct all minors misalignments. The strategy is illustrated on tomographic experiments performed on sections from plastic-embedded biological samples. The efficiency in correcting the misalignment of gold particles and in improving the quality of the reconstruction is documented both visually and quantitatively. In our approach every region of the tomogram is associated with its own orientation parameters and can be eventually reconstructed with the preferred algorithm. This is convenient in the computation of 3D averages of equivalent structures. A simulation experiment is presented to show that the performances of this approach are superior to those of the method of rotation in direct space.


Expression of a functional high-affinity IgG receptor, Fc gamma RI, on human mast cells: Up-regulation by IFN-gamma.
Biologically relevant activation of human mast cells through Fc receptors is believed to occur primarily through the high-affinity IgE receptor Fc epsilon RI. However, the demonstration in animal models that allergic reactions do not necessarily require Ag-specific IgE, nor the presence of a functional IgE receptor, and the clinical occurrence of some allergic reactions in situations where Ag-specific IgE appears to be lacking, led us to examine the hypothesis that human mast cells might express the high-affinity IgG receptor Fc gamma RI and in turn be activated through aggregation of this receptor. We thus first determined by RT-PCR that resting human mast cells exhibit minimal message for Fc gamma RI. We next found that IFN-gamma up-regulated the expression of Fc gamma RI. This was confirmed by flow cytometry, where Fc gamma RI expression on human mast cells was increased from approximately 2 to 44% by IFN-gamma exposure. Fc epsilon RI, Fc gamma RII, and Fc gamma RIII expression was not affected. Scatchard plots were consisted with these data where the average binding sites for monomeric IgG1 (Ka = 4-5 x 108 M-1) increased from approximately 2,400 to 12,100-17,300 per cell. Aggregation of Fc gamma RI on human mast cells, and only after IFN-gamma exposure, led to significant degranulation as evidenced by histamine release (24.5 +/- 4.4%): and up-regulation of mRNA expression for specific cytokines including TNF-alpha, GM-CSF, IL-3 and IL-13. These findings thus suggest another mechanism by which human mast cells may be recruited into the inflammatory processes associated with some immunologic and infectious diseases.


Recent progress in multi-electrode spike sorting methods.
In recent years, arrays of extracellular electrodes have been developed and manufactured to record simultaneously from hundreds of electrodes packed with a high density. These recordings should allow neuroscientists to reconstruct the individual activity of the neurons spiking in the vicinity of these electrodes, with the help of signal processing algorithms. Algorithms need to solve a source separation problem, also known as spike sorting. However, these new devices challenge the classical way to do spike sorting. Here we review different methods that have been developed to sort spikes from these large-scale recordings. We describe the common properties of these algorithms, as well as their main differences. Finally, we outline the issues that remain to be solved by future spike sorting algorithms.


Hepatoprotective properties of the Indian gooseberry (Emblica officinalis Gaertn): a review.
Liver diseases characterized by inflammation or tissue damage affect the optimal functioning and increase the morbidity and mortality of the affected individual. Liver diseases are a largely neglected health issue and recent reports indicate that they affect over 10% of the world population, with the highest burden in low and middle income countries that have minimal medical resources. To complicate matters the currently available pharmacological therapies are not optimal and when used for extended periods of time impart systemic toxicity. Diet can modify pathophysiological processes, including those of hepatotoxins, and studies have shown that some dietary constituents can afford heptoprotection. Emblica officinalis Gaertn or Phyllanthus emblica Linn, commonly known as the Indian gooseberry in English or amla in Hindi, is one of the most important medicinal and dietary plants in the Indian subcontinent. The fruits are of dietary and medicinal use and have wide applications in both traditional and folk systems of medicine. Scientific studies have shown amla to be effective in preventing/ameliorating the toxic effects of hepatotoxic agents like ethanol, paracetamol, carbon tetrachloride, heavy metals, ochratoxins, hexachlorocyclohexane, antitubercular drugs and hepatotoxicity resulting from iron overload. Amla is also reported to impart beneficial effects on liver function and to mitigate hyperlipidemia and metabolic syndrome. Amla possesses protective effects against chemical-induced hepatocarcinogenesis in animal models of study. Additionally, the phytochemicals quercetin, gallic acid, corilagin and ellagic acid are also reported to protect against the cytotoxic effects of paracetamol, microcystins, galactosamine and lipopolysaccharide. The hepatoprotective actions of amla appear to be mediated by its free radical scavenging, antioxidant, anti-inflammatory and modulation of the xenobiotic detoxification process and lipid metabolism.


Biocomposites of non-crosslinked natural and synthetic polymers.
Biocomposite films comprising a non-crosslinked, natural polymer (collagen) and a synthetic polymer, poly(epsilon-caprolactone) (PCL), have been produced by impregnation of lyophilised collagen mats with a solution of PCL in dichloromethane followed by solvent evaporation. This approach avoids the toxicity problems associated with chemical crosslinking. Distinct changes in film morphology, from continuous surface coating to open porous format, were achieved by variation of processing parameters such as collagen:PCL ratio and the weight of the starting lyophilised collagen mat. Collagenase digestion indicated that the collagen content of 1:4 and 1:8 collagen:PCL biocomposites was almost totally accessible for enzymatic digestion indicating a high degree of collagen exposure for interaction with other ECM proteins or cells contacting the biomaterial surface. Much reduced collagen exposure (around 50%) was measured for the 1:20 collagen:PCL materials. These findings were consistent with the SEM examination of collagen:PCL biocomposites which revealed a highly porous morphology for the 1:4 and 1:8 blends but virtually complete coverage of the collagen component by PCL in the 1:20 samples. Investigations of the attachment and spreading characteristics of human osteoblast (HOB) cells on PCL films and collagen:PCL materials respectively, indicated that HOB cells poorly recognised PCL but attachment and spreading were much improved on the biocomposites. The non-chemically crosslinked, collagen:PCL biocomposites described are expected to provide a useful addition to the range of biomaterials and matrix systems for tissue engineering.


Expression of the labial group Hox gene HrHox-1 and its alteration induced by retinoic acid in development of the ascidian Halocynthia roretzi.
Ascidian embryogenesis shares several developmental features with vertebrates. Thus, it is presumed that some molecular mechanisms that are critical for vertebrate development may also act in the early development of ascidians. Here, we investigated expression of the ascidian labial group Hox gene HrHox-1 in the development of Halocynthia roretzi. HrHox-1 showed a spatially restricted expression pattern along the anterior-posterior axis, which is remarkably similar to that of the vertebrate gene, Hoxb-1. The expression of HrHox-1, however, was exclusively in tissues of ectoderm origin unlike its vertebrate counterpart. Exposure of the embryos to 10(-6) M all-trans retinoic acid induced a larval phenotype with elimination of the anteriormost structures, the papillae. In this phenotype, the level of HrHox-1 expression was enhanced and ectopic expression was observed at the anterior terminal epidermis where the papillae are otherwise formed. These observations suggest that there are some conserved mechanisms in the spatial regulation of expression of labial group genes in embryogenesis of ascidians and vertebrates.


Distributed coordination of networked fractional-order systems.
This paper studies the distributed coordination of networked fractional-order systems over a directed interaction graph. A general fractional-order coordination model is introduced by summarizing three different cases: 1) fractional-order agent dynamics with integer-order coordination algorithms; 2) fractional-order agent dynamics with fractional-order coordination algorithms; and 3) integer-order agent dynamics with fractional-order coordination algorithms. We show sufficient conditions on the interaction graph and the fractional order such that coordination can be achieved using the general model. The coordination equilibrium is also explicitly given. In addition, we characterize the relationship between the number of agents and the fractional order to ensure coordination. Furthermore, we compare the convergence speed of coordination for fractional-order systems with that for integer-order systems. It is shown that the convergence speed of the fractional-order coordination algorithms can be improved by varying the fractional orders with time. Finally, simulation results are presented as a proof of concept.


Schizophrenia and depression, two poles of endocannabinoid system deregulation.
The activity of certain G protein-coupled receptors (GPCRs) and of glutamate N-Methyl-D-aspartate receptors (NMDARs) is altered in both schizophrenia and depression. Using postmortem prefrontal cortex samples from subjects with schizophrenia or depression, we observed a series of opposite changes in the expression of signaling proteins that have been implicated in the cross-talk between GPCRs and NMDARs. Thus, the levels of HINT1 proteins and NMDAR NR1 subunits carrying the C1 cytosolic segment were increased in depressives and decreased in schizophrenics, respect to matched controls. The differences in NR1 C1 subunits were compensated for via altered expression of NR1 subunits lacking the C1 segment; thus, the total number of NR1 subunits was comparable among the three groups. GPCRs influence the function of NR1 C1-containing NMDARs via PKC/Src, and thus, the association of mu-opioid and dopamine 2 receptors with NR1 C1 subunits was augmented in depressives and decreased in schizophrenics. However, the association of cannabinoid 1 receptors (CB1Rs) with NR1 C1 remained nearly constant. Endocannabinoids, via CB1Rs, control the presence of NR1 C1 subunits in the neural membrane. Thus, an altered endocannabinoid system may contribute to the pathophysiology of schizophrenia and depression by modifying the HINT1-NR1 C1/GPCR ratio, thereby altering GPCR-NMDAR cross-regulation.


The distribution of fitness effects of new mutations.
The distribution of fitness effects (DFE) of new mutations is a fundamental entity in genetics that has implications ranging from the genetic basis of complex disease to the stability of the molecular clock. It has been studied by two different approaches: mutation accumulation and mutagenesis experiments, and the analysis of DNA sequence data. The proportion of mutations that are advantageous, effectively neutral and deleterious varies between species, and the DFE differs between coding and non-coding DNA. Despite these differences between species and genomic regions, some general principles have emerged: advantageous mutations are rare, and those that are strongly selected are exponentially distributed; and the DFE of deleterious mutations is complex and multi-modal.


Epidemiology of osteoporosis.
Osteoporosis represents a major public health problem through its association with fragility fractures. All osteoporotic fractures increase patient morbidity; however, fractures of the hip and vertebrae are also linked with significant mortality. The public health burden of osteoporotic fracture is likely to rise in future generations, due in part to an increase in life expectancy. Understanding the epidemiology of this disease is therefore essential in trying to develop strategies to help reduce this load. This chapter will review the epidemiology of osteoporosis, including the relationship between low bone mass and fracture. It will review the epidemiology of fractures, concentrating on the sites where the majority of age-related fractures occur. Finally it will discuss new developments in the assessment of fracture risk.


Sacral fractures: classification and management.
Sacral fractures are a common component of pelvic fracture patterns and are an increasingly diagnosed injury both due to increased utilization of CT in trauma evaluation as well as an increasing rate of sacral fragility fractures as a result of an increase in general population age. Innovations in minimally invasive surgical techniques have also resulted in an increasing number of sacral fractures undergoing surgical management. It is vital that physicians practicing in an emergency setting are aware of the injury patterns and management of this increasingly injured and treated component of the bony pelvis. This article reviews the sacral anatomy as well as discusses the role of imaging and imaging appearance of sacral fractures. Sacral fracture patterns are described along with both historic and newer classification systems for sacral fractures and current management of sacral fracture.


Population Pharmacokinetics and Pharmacodynamics of Praziquantel in Ugandan Children with Intestinal Schistosomiasis: Higher Dosages Are Required for Maximal Efficacy.
Each year, millions of African children receive praziquantel (PZQ) by mass drug administration (MDA) to treat schistosomiasis at a standard single dose of 40 mg/kg of body weight, a direct extrapolation from studies of adults. A higher dose of 60 mg/kg is also acceptable for refractory cases. We conducted the first PZQ pharmacokinetic (PK) and pharmacodynamic (PD) study in young children comparing dosing. Sixty Ugandan children aged 3 to 8 years old with egg patent Schistosoma mansoni received PZQ at either 40 mg/kg or 60 mg/kg. PK parameters of PZQ racemate and enantiomers (R and S) were quantified. PD outcomes were assessed by standard fecal egg counts and novel schistosome-specific serum (circulating anodic antigen [CAA]) and urine (circulating cathodic antigen [CCA]) antigen assays. Population PK and PD analyses were performed to estimate drug exposure in individual children, and the relationship between drug exposure and parasitological cure was estimated using logistic regression. Monte Carlo simulations were performed to identify better, future dosing regimens. There was marked PK variability between children, but the area under the concentration-time curve (AUC) of PZQ was strongly predictive of the parasitological cure rate (CR). Although no child achieved antigenic cure, which is suggestive of an important residual adult worm burden, higher AUC was associated with greater CAA antigenic decline at 24 days. To optimize the performance of PZQ, analysis of our simulations suggest that higher doses (>60 mg/kg) are needed, particularly in smaller children. Schistosomiasis is a neglected tropical disease, typically associated with chronic morbidity, and its control is a global health priority. Praziquantel (PZQ) is the only available antiparasitic drug and is often given out, as a single oral dose (40 mg/kg), to school-aged children by mass drug administration (MDA) schemes operating within preventive chemotherapy campaigns as endorsed by the World Health Organization (WHO). This current strategy has several limitations. (i) It excludes preschool children who can be patently infected. (ii) It delivers PZQ at a dose directly extrapolated from adult pharmacological studies. To address these problems, we conducted the first pharmacokinetic and pharmacodynamic study of young children within an area of Uganda where Schistosoma mansoni is hyperendemic. Our results demonstrate that a higher dose (>60 mg/kg) is required, especially in smaller children, and draw attention to the need for further optimization of PZQ treatment based on schistosome antigenic assays, which are more sensitive to pharmacodynamic markers.


Quantifying technical skills during open operations using video-based motion analysis.
Objective quantification of technical operative skills in surgery remains poorly defined, although the delivery of and training in these skills is essential to the profession of surgery. Attempts to measure hand kinematics to quantify operative performance primarily have relied on electromagnetic sensors attached to the surgeon's hand or instrument. We sought to determine whether a similar motion analysis could be performed with a marker-less, video-based review, allowing for a scalable approach to performance evaluation. We recorded six reduction mammoplasty operations-a plastic surgery procedure in which the attending and resident surgeons operate in parallel. Segments representative of surgical tasks were identified with Multimedia Video Task Analysis software. Video digital processing was used to extract and analyze the spatiotemporal characteristics of hand movement. Attending plastic surgeons appear to use their nondominant hand more than residents when cutting with the scalpel, suggesting more use of countertraction. While suturing, attendings were more ambidextrous, with smaller differences in movement between their dominant and nondominant hands than residents. Attendings also seem to have more conservation of movement when performing instrument tying than residents, as demonstrated by less nondominant hand displacement. These observations were consistent within procedures and between the different attending plastic surgeons evaluated in this fashion. Video motion analysis can be used to provide objective measurement of technical skills without the need for sensors or markers. Such data could be valuable in better understanding the acquisition and degradation of operative skills, providing enhanced feedback to shorten the learning curve.


Triple rule-out CT in the emergency department: protocols and spectrum of imaging findings.
Triage decisions in patients suffering from acute chest pain remain a challenge. The patient's history, initial cardiac enzyme levels, or initial electrocardiograms (ECG) often do not allow selecting the patients in whom further tests are needed. Numerous vascular and non-vascular chest problems, such as pulmonary embolism (PE), aortic dissection, or acute coronary syndrome, as well as pulmonary, pleural, or osseous lesions, must be taken into account. Nowadays, contrast-enhanced multi-detector-row computed tomography (CT) has replaced previous invasive diagnostic procedures and currently represents the imaging modality of choice when the clinical suspicion of PE or acute aortic syndrome is raised. At the same time, CT is capable of detecting a multitude of non-vascular causes of acute chest pain, such as pneumonia, pericarditis, or fractures. Recent technical advances in CT technology have also shown great advantages for non-invasive imaging of the coronary arteries. In patients with acute chest pain, the optimization of triage decisions and cost-effectiveness using cardiac CT in the emergency department have been repetitively demonstrated. Triple rule-out CT denominates an ECG-gated protocol that allows for the depiction of the pulmonary arteries, thoracic aorta, and coronary arteries within a single examination. This can be accomplished through the use of a dedicated contrast media administration regimen resulting in a simultaneous attenuation of the three vessel territories. This review is intended to demonstrate CT parameters and contrast media administration protocols for performing a triple rule-out CT and discusses radiation dose issues pertinent to the protocol. Typical life-threatening and non-life-threatening diseases causing acute chest pain are illustrated.


Minimal tethered cord syndrome associated with thickening of the terminal filum.
The authors investigated the occurrence of anatomical abnormalities of the terminal filum in children undergoing surgical filum lysis for minimal tethered cord syndrome (TCS). Five consecutive children (age range 6-12 years) with medically refractory voiding dysfunction but no magnetic resonance (MR) imaging-documented lumbosacral abnormality on 1.5-tesla sequences underwent preoperative urodynamic studies consisting of calibrated uroflowmetry, cystometrography, and voiding cystourethrography. Urodynamic bladder function was abnormal in each case. A sixth child (5 years of age) who had progressive lower-extremity weakness, gait abnormality, and voiding dysfunction, but in whom there was no MR imaging-documented lumbosacral abnormality, was also included. These six children experienced improved bladder function after terminal filum lysis. Histologically, the terminal filum in these patients was fattier, thicker, and more densely fibrous than that in three reference patients undergoing incidental terminal filum lysis during selective dorsal rhizotomy or resection of a lumbar dermal sinus tract. All four patients with voiding dysfunction who underwent postoperative urodynamic testing experienced corresponding improvement in bladder function. Significant improvement of voiding dysfunction after surgical lysis of the terminal filum in children with MR imaging-documented normal lumbosacral spines was observed. In such children, in whom neurogenic dysfunction is identified by urodynamic testing, structural abnormalities of the terminal filum may exist. A prospective randomized controlled study of children undergoing surgical terminal filum lysis in cases of minimal TCS should be undertaken.


Simplified medical abortion screening: a demonstration project.
The objectives were to evaluate the safety and acceptability of outpatient medical abortion in selected women without a pretreatment ultrasound or pelvic examination. We conducted a prospective case-series study to estimate the incidence of serious adverse events (death, life-threatening event, hospitalization, transfusion or any other medical problem that we judged to be significant), surgical completion of the abortion and satisfaction in women provided with medical abortion without a pretreatment ultrasound or pelvic examination. We enrolled 406 women requesting medical abortion in Moldova, Mexico and the United States. To be eligible, a woman must have been certain that her last menstrual period started within the prior 56days, have had regular menses before the pregnancy, not have used hormonal contraceptives in the prior 2months (in the United States and Mexico) or 3months (in Moldova), have no risk factors for or symptoms of ectopic pregnancy, and not have had an ultrasound or pelvic exam in this pregnancy. One site also excluded women with uterine enlargement on abdominal palpation. Each participant received mifepristone (200mg orally) and misoprostol (400 mcg sublingually in Moldova; 800 mcg buccally at all other sites) and was followed until complete abortion, defined as requiring no further treatment. Of the 365 (90%) participants who provided sufficient follow-up information for analysis, 347 (95%) had complete abortion without additional treatment, 5 (1%) had surgical aspiration, and 10 (3%) had extra misoprostol. Three participants (1%) had serious adverse events; these included two hospital admissions for heavy bleeding managed with aspiration and one diagnosis of persistent gestational sac 19days after enrollment. Most (317, 90%) participants were pleased with omitting the pretreatment ultrasound and pelvic exam. In this study, medical abortion without screening ultrasound or pelvic exam resulted in no serious adverse events that were likely to have been prevented by those tests and was highly acceptable. Screening for medical abortion without exam or ultrasound shows promise as a means for increasing access to this service. More research is needed to develop screening criteria that are more inclusive and simpler for clinical use.


Learning Spatiotemporally Encoded Pattern Transformations in Structured Spiking Neural Networks.
Information encoding in the nervous system is supported through the precise spike timings of neurons; however, an understanding of the underlying processes by which such representations are formed in the first place remains an open question. Here we examine how multilayered networks of spiking neurons can learn to encode for input patterns using a fully temporal coding scheme. To this end, we introduce a new supervised learning rule, MultilayerSpiker, that can train spiking networks containing hidden layer neurons to perform transformations between spatiotemporal input and output spike patterns. The performance of the proposed learning rule is demonstrated in terms of the number of pattern mappings it can learn, the complexity of network structures it can be used on, and its classification accuracy when using multispike-based encodings. In particular, the learning rule displays robustness against input noise and can generalize well on an example data set. Our approach contributes to both a systematic understanding of how computations might take place in the nervous system and a learning rule that displays strong technical capability.


A comparative online survey on the intention to get COVID-19 vaccine between Greek and Cypriot healthcare personnel: is the country a predictor?
Vaccine hesitancy amongst healthcare personnel (HCP) is a critical issue. The aim was to explore the factors that determine the intention to opt for COVID-19 vaccine among HCP from two southern European countries. An anonymous online self-administered survey using Google Forms has been conducted between December 1st to December 15th, 2020 among the HCP in Greece and the Republic of Cyprus. A total of 2,238 HCPs participated in the study (1,220/54.5% from Republic of Cyprus and 1,018 from Greece). Overall 1,082 (48.3%) stressed their intention to get vaccinated (64.4% for Greece and 34.9% for Republic of Cyprus). The main reasons for those who intend to get the COVID-19 vaccine include self (94.2%), family (98.7%), and patients protection (95.2%) as well as mitigation of COVID-19 pandemic (95.4%). The multivariate logistic regression that was performed for the total sample revealed that the following variables were significantly associated with an increased probability to get vaccinated against COVID-19: being a physician, a member of the nursing personnel, paramedical staff, working in Greece, age, the belief that influenza vaccination should be mandatory for HCP, and the rating of the overall management of COVID-19 pandemic in the country and from the public hospitals. Physicians were more likely to get vaccinated against COVID-19 than other HCP. The age was a predictor of COVID-19 uptake intention in the Republic of Cyprus. The belief that there was a successful management of the COVID-19 pandemic contributed to the intention to COVID-19 vaccination uptake.


What could family income be if health insurance were more affordable?
Adjusted for inflation, household income has been relatively flat since the mid-1990s, but the inflation rate of employer-sponsored health insurance has been greater than both household income growth and general inflation for 50 years. We estimated the effect on average family income if health insurance inflation matched the general inflation rate since 1996, and those savings were given to employees as income. We used data from the Medical Expenditure Panel Survey, the Milliman Medical Index, and other federal sources to model the relationship between private health insurance costs and household income over the last 15 years. If the cost of family health care costs had kept pace with the Consumer Price Index (CPI) rate since 1996, the average family income could have been $8,410 higher in 2010 ($68,805 versus $60,395), 13.9% more than actual earnings. If health care costs had not exceeded the CPI rate since 1996 and if all the excess costs were converted into employee wages, median family income could be substantially higher today.


Neutropenia-related costs in patients treated with first-line chemotherapy for advanced non-small cell lung cancer.
Neutropenia is a major adverse event often associated with chemotherapy administration. Neutropenia-related complications often lead to increased use of costly health care including inpatient and outpatient services. Monitoring and treatment of neutropenia thus place an economic burden on the health care system. To evaluate (a) costs and medical resource use for chemotherapy- related afebrile and febrile neutropenia in an elderly population with Stage IIIB or Stage IV non-small cell lung cancer (NSCLC), and (b) costs unrelated to neutropenia and total all-cause health care costs during first-line chemotherapy. Study patients in this retrospective database analysis were aged 65 years or older with a diagnosis of Stage IIIB or Stage IV NSCLC in the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1998 through 2002. Neutropenia was identified by the presence of a primary or secondary diagnosis code for diseases of white blood cells (ICD-9-CM = 288.xx) during a period of first-line chemotherapy treatment. Febrile neutropenia was defined by (a) an inpatient hospitalization with a primary or secondary diagnosis for neutropenia occurring at any time during first-line chemotherapy or (b) intravenous or intramuscular antibiotic administration occurring after the initial neutropenia diagnosis and during first-line chemotherapy. Patients with neutropenia without these events were considered to have afebrile neutropenia. Patients were followed in the SEER-Medicare database to evaluate costs (defined as all Medicare payments, primary insurer payments, and patient copayments and deductibles) and resource use associated with afebrile or febrile neutropenia while on first-line chemotherapy. If a patient switched to second-line chemotherapy, the day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. Costs were summed for 2 main types of cost measures: neutropenia-related costs, defined as costs for claims with either a primary or secondary diagnosis of neutropenia, and costs unrelated to neutropenia. Costs were classified using ICD-9-CM diagnosis and procedure codes appearing on the claims, with confidence intervals [CIs] for cost measures estimated by using nonparametric bootstrapping methods. Group comparisons of patient characteristics, medical utilization, and cost study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category for comparisons involving patient characteristic, medical utilization, and total all-cause health care cost study measures. For total neutropenia-related costs, afebrile and febrile neutropenia study groups were compared. Among elderly patients treated first-line for advanced NSCLC, 5,138 met inclusion criteria, of whom 1,228 (23.9%) developed afebrile (n = 740, 14.4%) or febrile neutropenia (n = 488, 9.5%) while on first-line chemotherapy. Mean per patient costs for treating neutropenia during first-line chemotherapy were $12,148 (standard deviation [SD] = $15,432, 95% confidence interval [CI] = $10,915-$13,607) for patients with febrile neutropenia and $3,099 (SD = $4,541, 95% CI = $2,796-$3,431) for patients with afebrile neutropenia (P<0.001), with mean (SD) length of follow-up (duration of first-line chemotherapy) of 4.5 (4.8) and 5.5 (7.0) months, respectively. Expressed as a percentage of total all-cause health care costs during first-line chemotherapy, neutropenia-related costs accounted for 32.2% of total costs for patients with febrile neutropenia (mean [SD] = $37,694 [$26,078]) and 9.1% of total costs for patients with afebrile neutropenia (mean [SD] = $34,204 [$26,317]). Mean neutropenia-related costs per patient per month (PPPM) during first-line chemotherapy were $2,700 for patients with febrile neutropenia and $563 for patients with afebrile neutropenia. PPPM costs unrelated to neutropenia for patients with afebrile neutropenia, febrile neutropenia, and no neutropenia, respectively, were $5,655, $5,677, and $6,146. In sensitivity analyses, results were highly sensitive to the definition of neutropenia (i.e., claims with primary diagnosis only vs. primary or secondary diagnosis) but insensitive to the type of chemotherapy regimen. Neutropenia is a major adverse event that places patients at an increased risk of infection and subsequent morbidity and mortality. For elderly patients undergoing first-line chemotherapy for NSCLC, neutropenia, particularly febrile neutropenia, is associated with substantially higher total all-cause health care costs.


How to improve public participation in disaster risk management: A case study of Buein Zahra, a small city in Iran.
Identifying and providing basic solutions using a collaborative approach in earthquake-stricken cities of Iran has not yet been addressed. This article focuses on an area of practice and views disaster risk management from the point of view of volunteer groups to illustrate how the main components of disaster risk management affect the strengthening of public participation. In this article, Buein Zahra, a small city in Iran, is considered as a high-risk earthquake zone. The basic components of risk management are identified, namely public awareness, knowledge, skills, enabling environment, organisational development and social participation. An assessment of these indicators was done, and multidimensional relationships were established between them to enable an increase in the capacity for public participation. Accordingly, the results indicate that a mere increase in public awareness and knowledge, as seen today, and an improvement in enabling environment, although affecting disaster risk reduction, cannot by themselves lead to real public participation. Organisational development and strengthening of crisis coping skills are two key components to improving participation during crises in the small cities of Iran. According to the results of this study, institutional capacity and unreal political commitment have caused inefficiency of public participation in earthquake preparedness.


Attention to Distinct Goal-relevant Features Differentially Guides Semantic Knowledge Retrieval.
A critical aspect of conceptual knowledge is the selective activation of goal-relevant aspects of meaning. Although the contributions of ventrolateral prefrontal and posterior temporal areas to semantic cognition are well established, the precise role of posterior parietal cortex in semantic control remains unknown. Here, we examined whether this region modulates attention to goal-relevant features within semantic memory according to the same principles that determine the salience of task-relevant object properties during visual attention. Using multivoxel pattern analysis, we decoded attentional referents during a semantic judgment task, in which participants matched an object cue to a target according to concrete (i.e., color, shape) or abstract (i.e., function, thematic context) semantic features. The goal-relevant semantic feature participants attended to (e.g., color or shape, function or theme) could be decoded from task-associated cortical activity with above-chance accuracy, a pattern that held for both concrete and abstract semantic features. A Bayesian confusion matrix analysis further identified differential contributions to representing attentional demands toward specific object properties across lateral prefrontal, posterior temporal, and inferior parietal regions, with the dorsolateral pFC supporting distinctions between higher-order properties and the left intraparietal sulcus being the only region supporting distinctions across all semantic features. These results are the first to demonstrate that patterns of neural activity in the parietal cortex are sensitive to which features of a concept are attended to, thus supporting the contributions of posterior parietal cortex to semantic control.


Diverse reactions of N-heterocyclic carbenes with an alkynylborane and isolation of a reactive zwitterionic borataallene.
Ethynyldimesitylborane (1) is synthesised via salt elimination and its reactivity towards NHCs is studied. Depending on their size, NHCs attack either at the boron atom or at the β-alkynyl carbon atom. Steric control over the reaction was probed by reactions with N-heterocyclic carbenes yielding a carbene-borane adduct (2), a 1-boraindane (3), and the first structurally characterised borataallene (4).


Mice homozygous for a targeted disruption of the proto-oncogene int-2 have developmental defects in the tail and inner ear.
We derived mice that carry a targeted insertion of a neor gene in the int-2 (Fgf-3) proto-oncogene coding sequences. The mutation was found to be recessive and mice that were homozygous for the insertion did not often survive to adulthood. The mutant mice had defects in the development of the tail and inner ear that could be correlated with disruption of int-2 expression in the posterior primitive streak and hindbrain or otic vesicle. While the tail phenotype was 100% penetrant, we found that the inner ear phenotype had reduced penetrance and variable expressivity. The variable expressivity could not be attributed to variability in the genetic background of the mutant allele or to leaky expression from the mutant allele. Thus, we conclude that even in a uniform genetic background, stochastic variation in the expression of a developmental circuit can result in dramatic differences in phenotypic consequences.


The microneme protein MIC4, or an MIC4-like protein, is expressed within the macrogamete and associated with oocyst wall formation in Toxoplasma gondii.
The expression and localisation of MIC4, or an immuno-cross reacting MIC4-like protein, was examined in the enteric forms of Toxoplasma gondii using immunocytochemistry. In addition to being located within the micronemes of the merozoites, MIC4 or the MIC4-like protein was present within the macrogamete and was associated with the developing oocyst wall. The macrogamete is characterised by two types of structurally distinct wall forming bodies (WFB1 and 2). However, by immuno-electron microscopy, it was possible to identify two populations of dense granules (WFB1) which appear to form sequentially during macrogamete development. The first granules to form (WFB1a) stained positively with anti-MIC4 and were followed by MIC4 negative granules (WFB1b). During oocyst wall formation, the WFB1a and b sequentially released their contents onto the surface with WFB1a material forming an anti-MIC4 positive outer veil, while the WFB1b forms the electron dense outer layer of the oocyst wall. The inner layer was formed by WFB2. Thus, for the first time, it was possible to identify two populations of dense granules (WFB1a and b) involved in the formation of different parts of the oocyst wall. It was not possible to analyse the contents of macrogametes by western blot to unequivocally identify the antigen recognised by the polyclonal antisera as MIC4.


The research productivity of Canadian physicians: how the timing of obtaining a PhD has an influence.
To determine whether the sequence of training to obtain MD and PhD degrees is associated with different career paths for physicians who have their PhD before medical school and those who obtain it after their MD, and to explore the factors that encourage or dissuade Canadian dual-degree physicians in pursuing a research career. In 2003, questionnaires from the University of Alberta, Edmonton, Canada, were sent to all 734 Canadian physicians having MDs and PhDs, identified through the Canadian Medical Directory. Data collected were gender; year and country of MD; sequence of obtaining degrees; portion of time on clinical, research, teaching, and administrative duties; number of publications and currently held grant amounts; and perceived incentives and disincentives to research careers. Two focus groups were held with a subset of physicians to further explore themes. The response rate was 64%. On the basis of the timing of the PhD relative to the MD, physicians were designated early PhDs (26%), concurrent PhDs (12%), or late PhDs (62%). Late PhDs spent more time in research and less time on clinical practice than the other two groups and spent more time teaching and had published more papers than the early PhDs. Grant amounts were highest for late PhDs. Lack of time and resources were the major disincentives to research, and noteworthy incentives were the opportunity for intellectual challenge and creativity, and previous research experience. Physicians who obtain a PhD after an MD have a more research-focused career than those who enter medical school with a PhD.