Impact of environmental DDT concentrations on gill adaptation to increased salinity in the tilapia Sarotherodon melanotheron.
Estuaries of tropical developing countries suffering from severe droughts induced by climate change are habitats to fish, which face drastic salinity variations and the contact with pollutants. The Western Africa tilapia Sarotherodon melanotheron is highly resistant to hypersalinity, but the effect of human-released xenobiotics on its adaptation is barely known. Controlled experiments were conducted to observe S. melanotheron gill adaptation to abrupt salinity variations in the presence of waterborne DDT, at concentrations detected in their natural habitat. The gills appeared as an important site of DDT conversion to DDD and/or depuration. A 12-days DDT exposure resulted in decreased gill epithelium thickness at all salinities (from fresh- to hypersaline-water), and the structure of gills from freshwater fish was particularly altered, relative to controls. No unbalance in tilapia blood osmolality was observed following DDT exposure, which however caused a decrease in branchial Na(+)-K(+)-ATPase (NKA) activity. Gill cellular NKA expression was reduced in salt-water, together with the expression of the CFTR chloride channel in hypersaline water. Although S. melanotheron seems very resistant (especially in seawater) to short-term waterborne DDT contamination, the resulting alterations of the gill tissue, cells and enzymes might affect longer term respiration, toxicant depuration and/or osmoregulation in highly fluctuating salinities.


Using creative co-design to develop a decision support tool for people with malignant pleural effusion.
Malignant pleural effusion (MPE) is a common, serious problem predominantly seen in metastatic lung and breast cancer and malignant pleural mesothelioma. Recurrence of malignant pleural effusion is common, and symptoms significantly impair people's daily lives. Numerous treatment options exist, yet choosing the most suitable depends on many factors and making decisions can be challenging in pressured, time-sensitive clinical environments. Clinicians identified a need to develop a decision support tool. This paper reports the process of co-producing an initial prototype tool. Creative co-design methods were used. Three pleural teams from three disparate clinical sites in the UK were involved. To overcome the geographical distance between sites and the ill-health of service users, novel distributed methods of creative co-design were used. Local workshops were designed and structured, including video clips of activities. These were run on each site with clinicians, patients and carers. A joint national workshop was then conducted with representatives from all stakeholder groups to consider the findings and outputs from local meetings. The design team worked with participants to develop outputs, including patient timelines and personas. These were used as the basis to develop and test prototype ideas. Key messages from the workshops informed prototype development. These messages were as follows. Understanding and managing the pleural effusion was the priority for patients, not their overall cancer journey. Preferred methods for receiving information were varied but visual and graphic approaches were favoured. The main influences on people's decisions about their MPE treatment were personal aspects of their lives, for example, how active they are, what support they have at home. The findings informed the development of a first prototype/service visualisation (a video representing a web-based support tool) to help people identify personal priorities and to guide shared treatment decisions. The creative design methods and distributed model used in this project overcame many of the barriers to traditional co-production methods such as power, language and time. They allowed specialist pleural teams and service users to work together to create a patient-facing decision support tool owned by those who will use it and ready for implementation and evaluation.


An intergenic risk locus containing an enhancer deletion in 2q35 modulates breast cancer risk by deregulating IGFBP5 expression.
Breast cancer is the most diagnosed malignancy and the second leading cause of cancer mortality in females. Previous association studies have identified variants on 2q35 associated with the risk of breast cancer. To identify functional susceptibility loci for breast cancer, we interrogated the 2q35 gene desert for chromatin architecture and functional variation correlated with gene expression. We report a novel intergenic breast cancer risk locus containing an enhancer copy number variation (enCNV; deletion) located approximately 400Kb upstream to IGFBP5, which overlaps an intergenic ERα-bound enhancer that loops to the IGFBP5 promoter. The enCNV is correlated with modified ERα binding and monoallelic-repression of IGFBP5 following oestrogen treatment. We investigated the association of enCNV genotype with breast cancer in 1,182 cases and 1,362 controls, and replicate our findings in an independent set of 62,533 cases and 60,966 controls from 41 case control studies and 11 GWAS. We report a dose-dependent inverse association of 2q35 enCNV genotype (percopy OR = 0.68 95%CI 0.55-0.83, P = 0.0002; replication OR = 0.77 95% CI 0.73-0.82, P = 2.1 × 10-19) and identify 13 additional linked variants (r2 > 0.8) in the 20Kb linkage block containing the enCNV (P = 3.2 × 10-15 - 5.6 × 10-17). These associations were independent of previously reported 2q35 variants, rs13387042/rs4442975 and rs16857609, and were stronger for ER-positive than ER-negative disease. Together, these results suggest that 2q35 breast cancer risk loci may be mediating their effect through IGFBP5.


Cellular redox pathways as a therapeutic target in the treatment of cancer.
The vulnerability of some cancer cells to oxidative signals is a therapeutic target for the rational design of new anticancer agents. In addition to their well characterized effects on cell division, many cytotoxic anticancer agents can induce oxidative stress by modulating levels of reactive oxygen species (ROS) such as the superoxide anion radical, hydrogen peroxide and hydroxyl radicals. Tumour cells are particularly sensitive to oxidative stress as they typically have persistently higher levels of ROS than normal cells due to the dysregulation of redox balance that develops in cancer cells in response to increased intracellular production of ROS or depletion of antioxidant proteins. In addition, excess ROS levels potentially contribute to oncogenesis by the mediation of oxidative DNA damage. There are several anticancer agents in development that target cellular redox regulation. The overall cellular redox state is regulated by three systems that modulate cellular redox status by counteracting free radicals and ROS, or by reversing the formation of disulfides; two of these are dependent on glutathione and the third on thioredoxin. Drugs targeting S-glutathionylation have direct anticancer effects via cell signalling pathways and inhibition of DNA repair, and have an impact on a wide range of signalling pathways. Of these agents, NOV-002 and canfosfamide have been assessed in phase III trials, while a number of others are undergoing evaluation in early phase clinical trials. Alternatively, agents including PX-12, dimesna and motexafin gadolinium are being developed to target thioredoxin, which is overexpressed in many human tumours, and this overexpression is associated with aggressive tumour growth and poorer clinical outcomes. Finally, arsenic derivatives have demonstrated antitumour activity including antiproliferative and apoptogenic effects on cancer cells by pro-oxidant mechanisms, and the induction of high levels of oxidative stress and apoptosis by an as yet undefined mechanism. In this article we review anticancer drugs currently in development that target cellular redox activity to treat cancer.


Unified approach to multipolar polarisation and charge transfer for ions: microhydrated Na+.
Electrostatic effects play a large part in determining the properties of chemical systems. In addition, a treatment of the polarisation of the electron distribution is important for many systems, including solutions of monatomic ions. Typically employed methods for describing polarisable electrostatics use a number of approximations, including atom-centred point charges and polarisation methods that require iterative calculation on the fly. We present a method that treats charge transfer and polarisation on an equal footing. Atom-centred multipole moments describe the charge distribution of a chemical system. The variation of these multipole moments with the geometry of the surrounding atoms is captured by the machine learning method kriging. The interatomic electrostatic interaction can be computed using the resulting predicted multipole moments. This allows the treatment of both intra- and interatomic polarisation with the same method. The proposed method does not return explicit polarisabilities but instead, predicts the result of the polarisation process. An application of this new method to the sodium cation in a water environment is described. The performance of the method is assessed by comparison of its predictions of atomic multipole moments and atom-atom electrostatic interaction energies to exact results. The kriging models are able to predict the electrostatic interaction energy between the ion and all water atoms within 4 kJ mol(-1) for any of the external test set Na(+)(H2O)6 configurations.


Sparse representation for color image restoration.
Sparse representations of signals have drawn considerable interest in recent years. The assumption that natural signals, such as images, admit a sparse decomposition over a redundant dictionary leads to efficient algorithms for handling such sources of data. In particular, the design of well adapted dictionaries for images has been a major challenge. The K-SVD has been recently proposed for this task and shown to perform very well for various grayscale image processing tasks. In this paper, we address the problem of learning dictionaries for color images and extend the K-SVD-based grayscale image denoising algorithm that appears in. This work puts forward ways for handling nonhomogeneous noise and missing information, paving the way to state-of-the-art results in applications such as color image denoising, demosaicing, and inpainting, as demonstrated in this paper.


Exceptionally prolonged tooth formation in elasmosaurid plesiosaurians.
Elasmosaurid plesiosaurians were globally prolific marine reptiles that dominated the Mesozoic seas for over 70 million years. Their iconic body-plan incorporated an exceedingly long neck and small skull equipped with prominent intermeshing 'fangs'. How this bizarre dental apparatus was employed in feeding is uncertain, but fossilized gut contents indicate a diverse diet of small pelagic vertebrates, cephalopods and epifaunal benthos. Here we report the first plesiosaurian tooth formation rates as a mechanism for servicing the functional dentition. Multiple dentine thin sections were taken through isolated elasmosaurid teeth from the Upper Cretaceous of Sweden. These specimens revealed an average of 950 daily incremental lines of von Ebner, and infer a remarkably protracted tooth formation cycle of about 2-3 years-other polyphyodont amniotes normally take ~1-2 years to form their teeth. Such delayed odontogenesis might reflect differences in crown length and function within an originally uneven tooth array. Indeed, slower replacement periodicity has been found to distinguish larger caniniform teeth in macrophagous pliosaurid plesiosaurians. However, the archetypal sauropterygian dental replacement system likely also imposed constraints via segregation of the developing tooth germs within discrete bony crypts; these partly resorbed to allow maturation of the replacement teeth within the primary alveoli after displacement of the functional crowns. Prolonged dental formation has otherwise been linked to tooth robustness and adaption for vigorous food processing. Conversely, elasmosaurids possessed narrow crowns with an elongate profile that denotes structural fragility. Their apparent predilection for easily subdued prey could thus have minimized this potential for damage, and was perhaps coupled with selective feeding strategies that ecologically optimized elasmosaurids towards more delicate middle trophic level aquatic predation.


Deletion analysis of the selfish B chromosome, Paternal Sex Ratio (PSR), in the parasitic wasp Nasonia vitripennis.
Paternal Sex Ratio (PSR) is a "selfish" B chromosome in the parasitoid wasp Nasonia vitripennis. It is transmitted via sperm, but causes supercondensation and destruction of the paternal chromosomes in early fertilized eggs. Because this wasp has haplodiploid sex determination, the effect of PSR is to convert diploid (female) eggs into haploid (male) eggs that carry PSR. Characterizing its genetic structure is a first step toward understanding mechanisms of PSR action. The chromosome is largely heterochromatic and contains several tandemly repeated DNA sequences that are not present on the autosomes. A deletion analysis of PSR was performed to investigate organization of repeats and location of functional domains causing paternal chromosome destruction. Deletion profiles using probes to PSR-specific repetitive DNA indicate that most repeats are organized in blocks on the chromosome. This study shows that the functional domains of PSR can be deleted, resulting in nonfunctional PSR chromosomes that are transmitted to daughters. A functional domain may be linked with the psr22 repeat, but function may also depend on abundance of PSR-specific repeats on the chromosome. It is hypothesized that the repeats act as a "sink" for a product required for proper paternal chromosome processing. Almost all deletion chromosomes remained either functional of nonfunctional in subsequent generations following their creation. One chromosome was exceptional in that it reverted from nonfunctionality to functionality in one lineage. Transmission rates of nonfunctional deletion chromosomes were high through haploid males, but low through diploid females.


Plasma volume expansion resulting from intravenous glucose tolerance test.
To quantify the degree of plasma volume expansion that occurs during an intravenous glucose tolerance test (IVGTT). Twenty healthy volunteers (mean age, 28 years) underwent IVGTTs in which 0.3 g/kg of glucose 30% was injected as a bolus over 1 min. Twelve blood samples were collected over 75 min. The plasma glucose and blood hemoglobin concentrations were used to calculate the volume distribution (V(d)) and the clearance (CL) of both the exogenous glucose and the injected fluid volume. The IVGTT caused a virtually instant plasma volume expansion of 10%. The half-life of the glucose averaged 15 min and the plasma volume expansion 16 min. Correction of the fluid kinetic model for osmotic effects after injection reduced CL for the infused volume by 85%, which illustrates the strength of osmosis in allocating fluid back to the intracellular fluid space. Simulations indicated that plasma volume expansion can be reduced to 60% by increasing the injection time from 1 to 5 min and reducing the glucose load from 0.3 to 0.2 g/kg. A regular IVGTT induced an acute plasma volume expansion that peaked at 10% despite the fact that only 50-80 mL of fluid were administered.


Obesity and cardiovascular disease: friend or foe?
Obesity is currently one of the greatest public health issues worldwide. However, despite its known deleterious effects on the cardiovascular system and its association with numerous cardiovascular diseases (CVD), recent findings leading to the development of concepts such as metabolically healthy obesity, the obesity paradox, and protective subcutaneous fat depots have raised a lively debate on the disparate effects of obesity on health outcomes. Regarding the concept of metabolically healthy obesity, by presumably labelling a subset of obese people as metabolically healthy, physicians may not feel pressed to curb the current obesity epidemic and prevent the next generation of people from becoming obese. Another issue is that the most commonly used anthropometric index to define obesity, the body mass index, is at the core of the controversy because of its limitations including its inability to discriminate between fat mass and muscle mass. Many recent epidemiological and metabolic studies have used other indices such as waist-hip ratio, waist circumference, and imaging (computed tomography or magnetic resonance imaging) measurements of visceral adiposity and of ectopic fat depots. In addition, emerging evidence supports the importance of cardiorespiratory fitness, skeletal muscle mass and strength in patients with obesity as useful variables to predict CVD risk beyond adiposity. In this review, we will discuss the complex and disparate effects of obesity on CVD, particularly focusing on whether, under given circumstances, it could be harmful, potentially harmless or neutral, or even possibly protective.


Optical distortions and birefringence in high power laser windows: model and computer code.
A general optical model is given which predicts optical wave front distortions and birefringence due to stress and temperature variations in laser heated and pressure loaded windows for cubic lattice window materials. A computer code is described that integrates stress and thermal computations with an optical model to predict the wave front distortions. Restrictive approximations, which have been used previously to predict window temperature and stress distributions, are avoided by using stress and thermal codes to predict these distributions within the windows. Comparisons between code predictions and experimental results are given.


Sprouty, an intracellular inhibitor of Ras signaling.
Sprouty was identified in a genetic screen as an inhibitor of Drosophila EGF receptor signaling. The Egfr triggers cell recruitment in the eye, and sprouty- eyes have excess photoreceptors, cone cells, and pigment cells. Sprouty's function is, however, more widespread. We show that it also interacts genetically with the receptor tyrosine kinases Torso and Sevenless, and it was first discovered through its effect on FGF receptor signaling. In contrast to an earlier proposal that Sprouty is extracellular, we show by biochemical analysis that Sprouty is an intracellular protein, associated with the inner surface of the plasma membrane. Sprouty binds to two intracellular components of the Ras pathway, Drk and Gap1. Our results indicate that Sprouty is a widespread inhibitor of Ras pathway signal transduction.


Effect of Gestational Diabetes Mellitus History on Future Pregnancy Behaviors: The Mutaba'ah Study.
Gestational diabetes mellitus (GDM) increases the risk of adverse pregnancy outcomes in any pregnancy and recurrence rates are high in future pregnancies. This study aims to investigate the effect of self-reported history of previous GDM on behaviors in a future pregnancy. This is an interim cross-sectional analysis of the pregnant women who participated in the Mutaba'ah Study between May 2017 and March 2020 in the United Arab Emirates. Participants completed a baseline self-administered questionnaire on sociodemographic and pregnancy-related information about the current pregnancy and previous pregnancies. Regression models assessed the relationships between self-reported history of GDM and pre-pregnancy and pregnancy behaviors in the current pregnancy. Out of 5738 pregnant parous women included in this analysis, nearly 30% (n = 1684) reported a history of GDM in a previous pregnancy. Women with a history of previous GDM were less likely to plan their current pregnancies (adjusted odds ratio (aOR): 0.84, 95% confidence interval (CI) 0.74-0.96) and more likely to be worried about childbirth (aOR: 1.18, 95% CI 1.03-1.36). They had shorter interpregnancy intervals between their previous child and current pregnancy (aOR: 0.88, 95% CI 0.82-0.94, per SD increase). There were no significant differences between women with and without a history of GDM in supplement use, sedentary behavior, or physical activity before and during this current pregnancy. Nearly a third of parous pregnant women in this population had a history of GDM in a previous pregnancy. Pregnant women with a previous history of GDM were similar to their counterparts with no history of GDM in the adopted pre-pregnancy and prenatal health behaviors. More intensive and long-term lifestyle counseling, possibly supported by e-health and social media materials, might be required to empower pregnant women with a history of GDM. This may assist in adopting and maintaining healthy prenatal behaviors early during the pregnancy or the preconception phase to minimize the risk of GDM recurrence and the consequential adverse maternal and infant health outcomes.


Even simple forms of social learning rely on intention attribution in marmoset monkeys (Callithrix jacchus).
Intention attribution guides the cognitively most demanding forms of social learning, such as imitation, thereby scaffolding cumulative cultural evolution. However, it is not thought to be necessary for more basic forms of social learning. Here we present evidence that in marmoset monkeys (Callithrix jacchus) even most basic forms of social learning such as enhancement depend on intention attribution. Marmosets perceived the behavior of a conspecific and a conspecific-like robot, but not that of a moving black box, as goal directed. Their subsequent choice behavior was shaped by social facilitation and stimulus enhancement, that is, by very simple forms of social learning, but only when exposed to the conspecific and robot, which they previously had perceived as intentional agents. We discuss the implications of this finding for contemporary debates about social learning, including emulation learning and ghost control studies, the necessity of goal-directed copying for cumulative cultural evolution, and the limits of current classification systems of social learning for the evolution of social and asocial learning.


Biogas production from hydrothermal liquefaction wastewater (HTLWW): Focusing on the microbial communities as revealed by high-throughput sequencing of full-length 16S rRNA genes.
Hydrothermal liquefaction (HTL) is an emerging and promising technology for the conversion of wet biomass into bio-crude, however, little attention has been paid to the utilization of hydrothermal liquefaction wastewater (HTLWW) with high concentration of organics. The present study investigated biogas production from wastewater obtained from HTL of straw for bio-crude production, with focuses on the analysis of the microbial communities and characterization of the organics. Batch experiments showed the methane yield of HTLWW (R-HTLWW) was 184 mL/g COD, while HTLWW after petroleum ether extraction (PE-HTLWW), to extract additional bio-crude, had higher methane yield (235 mL/g COD) due to the extraction of recalcitrant organic compounds. Sequential batch experiments further demonstrated the higher methane yield of PE-HTLWW. LC-TOF-MS, HPLC and gel filtration chromatography showed organics with molecular weight (MW) < 1000 were well degraded. Results from the high-throughput sequencing of full-length 16S rRNA genes analysis showed similar microbial community compositions were obtained for the reactors fed with either R-HTLWW or PE-HTLWW. The degradation of fatty acids were related with Mesotoga infera, Syntrophomonas wolfei et al. by species level identification. However, the species related to the degradation of other compounds (e.g. phenols) were not found, which could be due to the presence of uncharacterized microorganisms. It was also found previously proposed criteria (97% and 98.65% similarity) for species identification of 16S rRNA genes were not suitable for a fraction of 16S rRNA genes.


Protein-DNA interactions define the mechanistic aspects of circle formation and insertion reactions in IS2 transposition.
Transposition in IS3, IS30, IS21 and IS256 insertion sequence (IS) families utilizes an unconventional two-step pathway. A figure-of-eight intermediate in Step I, from asymmetric single-strand cleavage and joining reactions, is converted into a double-stranded minicircle whose junction (the abutted left and right ends) is the substrate for symmetrical transesterification attacks on target DNA in Step II, suggesting intrinsically different synaptic complexes (SC) for each step. Transposases of these ISs bind poorly to cognate DNA and comparative biophysical analyses of SC I and SC II have proven elusive. We have prepared a native, soluble, active, GFP-tagged fusion derivative of the IS2 transposase that creates fully formed complexes with single-end and minicircle junction (MCJ) substrates and used these successfully in hydroxyl radical footprinting experiments. In IS2, Step I reactions are physically and chemically asymmetric; the left imperfect, inverted repeat (IRL), the exclusive recipient end, lacks donor function. In SC I, different protection patterns of the cleavage domains (CDs) of the right imperfect inverted repeat (IRR; extensive in cis) and IRL (selective in trans) at the single active cognate IRR catalytic center (CC) are related to their donor and recipient functions. In SC II, extensive binding of the IRL CD in trans and of the abutted IRR CD in cis at this CC represents the first phase of the complex. An MCJ substrate precleaved at the 3' end of IRR revealed a temporary transition state with the IRL CD disengaged from the protein. We propose that in SC II, sequential 3' cleavages at the bound abutted CDs trigger a conformational change, allowing the IRL CD to complex to its cognate CC, producing the second phase. Corroborating data from enhanced residues and curvature propensity plots suggest that CD to CD interactions in SC I and SC II require IRL to assume a bent structure, to facilitate binding in trans. Different transpososomes are assembled in each step of the IS2 transposition pathway. Recipient versus donor end functions of the IRL CD in SC I and SC II and the conformational change in SC II that produces the phase needed for symmetrical IRL and IRR donor attacks on target DNA highlight the differences.


Cardiovascular tissue engineering I. Perfusion bioreactors: a review.
Tissue engineering is a fast-evolving field of biomedical science and technology with future promise to manufacture living tissues and organs for replacement, repair, and regeneration of diseased organs. Owing to the specific role of hemodynamics in the development, maintenance, and functioning of the cardiovascular system, bioreactors are a fundamental of cardiovascular tissue engineering. The development of perfusion bioreactor technology for cardiovascular tissue engineering is a direct sequence of previous historic successes in extracorporeal circulation techniques. Bioreactors provide a fluidic environment for tissue engineered tissue and organs, and guarantee their viability, maturation, biomonitoring, testing, storage, and transportation. There are different types of bioreactors and they vary greatly in their size, complexity, and functional capabilities. Although progress in design and functional properties of perfusion bioreactors for tissue engineered blood vessels, heart valves, and myocardial patches is obvious, there are some challenges and insufficiently addressed issues, and room for bioreactor design improvement and performance optimization. These challenges include creating a triple perfusion bioreactor for vascularized tubular tissue engineered cardiac construct; designing and manufacturing fluidics-based perfused minibioreactors; incorporation of systematic mathematical modeling and computer simulation based on computational fluid dynamics into the bioreactor designing process; and development of automatic systems of hydrodynamic regime control. Designing and engineering of built-in noninvasive biomonitoring systems is another important challenge. The optimal and most efficient perfusion and conditioning regime, which accelerates tissue maturation of tissue-engineered constructs also remains to be determined. This is a first article in a series of reviews on critical elements of cardiovascular tissue engineering technology describing the current status, unsolved problems, and challenges of bioreactor technology in cardiovascular tissue engineering and outlining future trends and developments.


Extending the cost-benefit model of thermoregulation: high-temperature environments.
The classic cost-benefit model of ectothermic thermoregulation compares energetic costs and benefits, providing a critical framework for understanding this process (Huey and Slatkin 1976 ). It considers the case where environmental temperature (T(e)) is less than the selected temperature of the organism (T(sel)), and it predicts that, to minimize increasing energetic costs of thermoregulation as habitat thermal quality declines, thermoregulatory effort should decrease until the lizard thermoconforms. We extended this model to include the case where T(e) exceeds T(sel), and we redefine costs and benefits in terms of fitness to include effects of body temperature (T(b)) on performance and survival. Our extended model predicts that lizards will increase thermoregulatory effort as habitat thermal quality declines, gaining the fitness benefits of optimal T(b) and maximizing the net benefit of activity. Further, to offset the disproportionately high fitness costs of high T(e) compared with low T(e), we predicted that lizards would thermoregulate more effectively at high values of T(e) than at low ones. We tested our predictions on three sympatric skink species (Carlia rostralis, Carlia rubrigularis, and Carlia storri) in hot savanna woodlands and found that thermoregulatory effort increased as thermal quality declined and that lizards thermoregulated most effectively at high values of T(e).


The right-to-die movement: extrapolating from the National Hemlock Society U.S.A. membership survey.
A national membership survey of Hemlock Society USA was conducted by Fox and Kamakahi (1995). Respondents (N=6398) were asked a variety of questions, but in this paper we perform a longitudinal analysis of the characteristics of Hemlock Society USA members. Hemlock Society USA members are divided into three 5-year cohorts: Early Joiners (11 or more years of membership), Middle Joiners (6 to 10 years membership), and Late Joiners (5 or fewer years of membership). Differences between cohorts are examined and extrapolations made regarding Hemlock Society USA and the Right-to-Die Movement. A series of one-way ANOVAs were used with Scheme post-hoc comparisons as heuristic tools for assessing between-cohort differences. Late Joiners are different from earlier members, but are more like other Hemlock Society USA members than the adult U.S. population at large. Hemlock Society USA members are essentially societal "elites" (based on socio-demographic variables) who work in social environments that are decidedly split on the issue of voluntary suicide and euthanasia.


Importance of Complete Pathology Reporting for Neuroendocrine Carcinoma: WHO Guidelines Are a Good Start but Not Enough.
Neuroendocrine carcinomas (NECs) are diagnosed through a combination of immunohistochemistry (IHC) and morphology according to WHO guidelines. The presence of these crucial components for classification in the pathology report is critical for appropriate understanding of the report especially since terminology and definitions of NEC have been changing a lot lately. The aim of this study is to assess the effect of WHO 2010 on the quality of pathology reporting for NEC and to assess the relevance of the criteria demanded. Patients registered with a NEC (gastrointestinal or unknown origin) in the Netherlands Cancer Registry (NCR) between 2008 and 2012 were included. Local pathology reports were reviewed for reporting of morphology and IHC comparing 2008-2010 (baseline) with 2011-2012. The diagnosis of NEC was confirmed according to WHO 2010, if synaptophysin or chromogranin were positive in a majority of cells and Ki-67 or mitotic count confirmed a grade 3 tumour. 591 patients were registered with a NEC in the NCR. 436 pathology reports were reviewed. 62.2% of reports described morphology, IHC and grading in accordance with WHO 2010. Reporting of these parameters increased from 50.0% in 2008 to 69.2% in 2012. Large-cell NEC could be confirmed in 45.0% of patients, increasing from 31.7% in 2008 to 56.7% in 2012 (p = 0.02). Other diagnoses included neuroendocrine tumour (NET) G1/2 13.3%, small-cell carcinoma 2.8%, no neuroendocrine neoplasm (NEN) 17.7%, NEN grade unknown 21.3%. Mean survival was 1.1 years in large cell NEC versus 2.2 years in NET G1/2 (p = 0.005). Implementation of the WHO 2010 guideline is associated with a significant increase in reporting parameters needed for classification. Stratification of patients is more reliable based on reports containing all parameters. Guidelines alone however are not enough to warrant complete reporting; synoptic reports might be needed.


Cut-and-Run: A Distinct Mechanism by which V(D)J Recombination Causes Genome Instability.
V(D)J recombination is essential to generate antigen receptor diversity but is also a potent cause of genome instability. Many chromosome alterations that result from aberrant V(D)J recombination involve breaks at single recombination signal sequences (RSSs). A long-standing question, however, is how such breaks occur. Here, we show that the genomic DNA that is excised during recombination, the excised signal circle (ESC), forms a complex with the recombinase proteins to efficiently catalyze breaks at single RSSs both in vitro and in vivo. Following cutting, the RSS is released while the ESC-recombinase complex remains intact to potentially trigger breaks at further RSSs. Consistent with this, chromosome breaks at RSSs increase markedly in the presence of the ESC. Notably, these breaks co-localize with those found in acute lymphoblastic leukemia patients and occur at key cancer driver genes. We have named this reaction "cut-and-run" and suggest that it could be a significant cause of lymphocyte genome instability.


Expansion of polyreactive B cells cross-reactive to HLA and self in the blood of a patient with kidney graft rejection.
Antibody rejection is often accompanied by nondonor HLA specific antibodies (NDSA) and self-reactive antibodies that develop alongside donor-specific antibodies (DSA). To determine the source of these antibodies, we immortalized 107 B-cell clones from a kidney transplant recipient with humoral rejection. Two of these clones reacted to HLA class I or MICA. Both clones were also reactive to self-antigens and a lysate of a kidney cell line, hence revealing a pattern of polyreactivity. Monoclonality was verified by the identification of a single rearranged immunoglobulin heavy chain variable region (VH) sequence for each clone. By tracking their unique CDR3 sequence, we found that one such polyreactive clone was highly expanded in the patient blood, representing ~0.2% of circulating B cells. The VH sequence of this clone showed evidence of somatic mutations that were consistent with its memory phenotype and its expansion. Lastly, the reactivity of the expanded polyreactive B-cell clone was found in the patient serum at time of rejection. In conclusion, we provide here proof of principle at the clonal level that human antibodies can cross-react to HLA and self. Our findings strongly suggest that polyreactive antibodies contribute to DSA, NDSA as well as autoantibodies, in transplant recipients.


Treatment with Huperzine A improves cognition in vascular dementia patients.
In the present study, we tested the efficacy and safety of Huperzine A in treatment of mild to moderate vascular dementia (VaD). This was a randomized, double-blinded, placebo-controlled study with 78 patients with mild to moderate VaD. The participants were randomized to receive either vitamin C (100-mg bid) as placebo (n = 39) or Huperzine A (0.1-mg bid) (n = 39) for 12 consecutive weeks. The mini-mental state examination (MMSE), clinical dementia rating (CDR), and activities of daily living (ADL) scores were used for the assessment of cognition. The assessments were made prior to treatment, and 4, 8, and 12 weeks of the treatment. The adverse effects of the treatment were also recorded. After 12 weeks of treatment, the MMSE, CDR, and ADL scores significantly improved in the Huperzine A group (P < 0.01 for all comparisons), whereas the placebo group did not show any such improvement (P > 0.05 for all comparisons). No serious adverse events were recorded during the treatment. Huperzine A can significantly improve the cognitive function in patients with mild to moderate vascular dementia. Further, the medicament is safe.


Fatal pneumonitis after treatment with docetaxel and trastuzumab.
Pneumonitis is a rare but serious complication of docetaxel treatment. We report a 63-year-old woman with locally advanced breast cancer who was treated with docetaxel and trastuzumab. After the first course she was admitted with febrile neutropenia that resolved rapidly. After the second course she was admitted again with fever and dyspnoea. Despite intensive treatment she died of respiratory failure three weeks later. Autopsy showed diffuse interstitial inflammation of both lungs consistent with drug-induced inflammation. Docetaxel treatment was the most likely cause. It is important to be aware of this toxicity, because the subtle warning signs can easily be mistaken for an opportunistic infection, and, if not recognised in time, the mortality rate is high.


Mitochondrial and nuclear phylogenies of Cervidae (Mammalia, Ruminantia): Systematics, morphology, and biogeography.
The family Cervidae includes 40 species of deer distributed throughout the northern hemisphere, as well as in South America and Southeast Asia. Here, we examine the phylogeny of this family by analyzing two mitochondrial protein-coding genes and two nuclear introns for 25 species of deer representing most of the taxonomic diversity of the family. Our results provide strong support for intergeneric relationships. To reconcile taxonomy and phylogeny, we propose a new classification where the family Cervidae is divided in two subfamilies and five tribes. The subfamily Cervinae is composed of two tribes: the tribe Cervini groups the genera Cervus, Axis, Dama, and Rucervus, with the Père David's deer (Elaphurus davidianus) included in the genus Cervus, and the swamp deer (Cervus duvauceli) placed in the genus Rucervus; the tribe Muntiacini contains Muntiacus and Elaphodus. The subfamily Capreolinae consists of the tribes Capreolini (Capreolus and Hydropotes), Alceini (Alces), and Odocoileini (Rangifer + American genera). Deer endemic to the New World fall in two biogeographic lineages: the first one groups Odocoileus and Mazama americana and is distributed in North, Central, and South America, whereas the second one is composed of South American species only and includes Mazama gouazoubira. This implies that the genus Mazama is not a valid taxon. Molecular dating suggests that the family originated and radiated in central Asia during the Late Miocene, and that Odocoileini dispersed to North America during the Miocene/Pliocene boundary, and underwent an adaptive radiation in South America after their Pliocene dispersal across the Isthmus of Panama. Our phylogenetic inferences show that the evolution of secondary sexual characters (antlers, tusk-like upper canines, and body size) has been strongly influenced by changes in habitat and behaviour.


Contributions of North American endophytes to the phylogeny, ecology, and taxonomy of Xylariaceae (Sordariomycetes, Ascomycota).
The Xylariaceae (Sordariomycetes) comprise one of the largest and most diverse families of Ascomycota, with at least 85 accepted genera and ca. 1343 accepted species. In addition to their frequent occurrence as saprotrophs, members of the family often are found as endophytes in living tissues of phylogenetically diverse plants and lichens. Many of these endophytes remain sterile in culture, precluding identification based on morphological characters. Previous studies indicate that endophytes are highly diverse and represent many xylariaceous genera; however, phylogenetic analyses at the family level generally have not included endophytes, such that their contributions to understanding phylogenetic relationships of Xylariaceae are not well known. Here we use a multi-locus, cumulative supermatrix approach to integrate 92 putative species of fungi isolated from plants and lichens into a phylogenetic framework for Xylariaceae. Our collection spans 1933 isolates from living and senescent tissues in five biomes across the continental United States, and here is analyzed in the context of previously published sequence data from described species and additional taxon sampling of type specimens from culture collections. We found that the majority of strains obtained in our surveys can be classified in the hypoxyloid and xylaroid subfamilies, although many also were found outside of these lineages (as currently circumscribed). Many endophytes were placed in lineages previously not known for endophytism. Most endophytes appear to represent novel species, but inferences are limited by potential gaps in public databases. By linking our data, publicly available sequence data, and records of ascomata, we identify many geographically widespread, host-generalist clades capable of symbiotic associations with diverse photosynthetic partners. Concomitant with such cosmopolitan host use and distributions, many xylariaceous endophytes appear to inhabit both living and non-living plant tissues, with potentially important roles as saprotrophs. Overall, our study reveals major gaps in the availability of multi-locus datasets and metadata for this iconic family, and provides new hypotheses regarding the ecology and evolution of endophytism and other trophic modes across the family Xylariaceae.


The potent peptide antagonist to angiogenesis, C16Y, and cisplatin act synergistically in the down-regulation of the Bcl-2/Bax ratio and the induction of apoptosis in human ovarian cancer cells.
Cisplatin is one of the most potent antitumor agents for ovarian cancer, but has also been implicated in normal tissue cytotoxicity. We examined the effect of cisplatin alone and in combination with C16Y, a newly-identified anti-angiogenic peptide from the NH2-terminal domains of the γ-chain of laminin-1, on the modulation of Bcl-2/Bax expression and induction of apoptosis in ovarian cancer cells (OVACAR3). C16Y did not elicit cell death of human umbilical vein endothelial cells (HUVECs). Cisplatin exerted a lethal effect with an EC50 of 10 µM in OVACAR3s. In the presence of 25 or 50 µg/ml of C16Y (a range which has no effect against HUVECs), the EC50 for cisplatin in OVACAR3s decreased to 3.5 and 2.0 µM, respectively. Using fluorescence-activated cell sorting (FACS) analysis of DNA stained OVACAR3s and terminal deoxynucleotide tranferase-mediated dUTP nick end-labeling (TUNEL), we found that even at concentrations of 1 and 3 µM cisplatin, C16Y at 10 and 25 µg/ml increased the incidence of apoptosis in OVACAR3s by 3-5-fold. Each drug had some measurable effect on Bax protein expression. Furthermore, Bcl-2 protein expression levels were markedly reduced by C16Y alone and cisplatin alone in a dose-dependent manner. The combination of C16Y and cisplatin resulted in a further dramatic reduction in Bcl-2, underscoring the pronounced synergy produced by cisplatin and C16Y together. On the other hand, C16Y did not activate any other signal transduction pathways that usually culminate in the activation of apoptosis, such as the p53, p21waf1, p73, ERK1/2 or PI3-AKT pathways. These observations suggest that the suppression of the Bcl-2/Bax ratio may play an important role in mediating the synergistic effect of cisplatin and C16Y on the induction of apoptosis in OVACAR3 cells.


Perception, representation and recognition: a holistic view of recognition.
It is clear that humans have mental representations of their spatial environments and that these representations are useful, if not essential, in a wide variety of cognitive tasks such as identification of landmarks and objects, guiding actions and navigation and in directing spatial awareness and attention. Determining the properties of mental representation has long been a contentious issue (see Pinker, 1984). One method of probing the nature of human representation is by studying the extent to which representation can surpass or go beyond the visual (or sensory) experience from which it derives. From a strictly empiricist standpoint what is not sensed cannot be represented; except as a combination of things that have been experienced. But perceptual experience is always limited by our view of the world and the properties of our visual system. It is therefore not surprising when human representation is found to be highly dependent on the initial viewpoint of the observer and on any shortcomings thereof. However, representation is not a static entity; it evolves with experience. The debate as to whether human representation of objects is view-dependent or view-invariant that has dominated research journals recently may simply be a discussion concerning how much information is available in the retinal image during experimental tests and whether this information is sufficient for the task at hand. Here we review an approach to the study of the development of human spatial representation under realistic problem solving scenarios. This is facilitated by the use of realistic virtual environments, exploratory learning and redundancy in visual detail.


Mechanotransduction across the cell surface and through the cytoskeleton.
Mechanical stresses were applied directly to cell surface receptors with a magnetic twisting device. The extracellular matrix receptor, integrin beta 1, induced focal adhesion formation and supported a force-dependent stiffening response, whereas nonadhesion receptors did not. The cytoskeletal stiffness (ratio of stress to strain) increased in direct proportion to the applied stress and required intact microtubules and intermediate filaments as well as microfilaments. Tensegrity models that incorporate mechanically interdependent struts and strings that reorient globally in response to a localized stress mimicked this response. These results suggest that integrins act as mechanoreceptors and transmit mechanical signals to the cytoskeleton. Mechanotransduction, in turn, may be mediated simultaneously at multiple locations inside the cell through force-induced rearrangements within a tensionally integrated cytoskeleton.


Are you ready for an office code blue? : online video to prepare for office emergencies.
Medical emergencies occur commonly in offices of family physicians, yet many offices are poorly prepared for emergencies. An Internet-based educational video discussing office emergencies might improve the responses of physicians and their staff to emergencies, yet such a tool has not been previously described. To use evidence-based practices to develop an educational video detailing preparation for emergencies in medical offices, disseminate the video online, and evaluate the attitudes of physicians and their staff toward the video. A 6-minute video was created using a review of recent literature and Canadian regulatory body policies. The video describes recommended emergency equipment, emergency response improvement, and office staff training. Physicians and their staff were invited to view the video online at www.OfficeEmergencies.ca. Viewers' opinions of the video format and content were assessed by survey (n = 275). Survey findings indicated the video was well presented and relevant, and the Web-based format was considered convenient and satisfactory. Participants would take other courses using this technology, and agreed this program would enhance patient care.


Childhood cancer incidence in South Africa, 1987-2007.
Childhood cancer is an emerging problem in Africa. Its extent is hazy because data are scarce, but it should be addressed. This is the first report from the South African Children's Tumour Registry (SACTR), which covers the whole of South Africa (SA). It provides minimal estimates of cancer incidence and discusses the challenges of cancer surveillance and control in a child population in a middle-income country. Only about 2% of the African population is covered by cancer registries producing comparable incidence data. To present and interpret incidence patterns and trends of childhood cancer over a 21-year period. The results should raise awareness of the problem of childhood cancer in an African population and provide sensible data for taking this problem in hand. All eligible and validated cancer cases registered in the SACTR over the period 1987-2007 and classified according to the International Classification of Childhood Cancer were included. Population data were retrieved from official sources and estimated for the population subcategories. Incidence rates were standardised to the world standard and time trends were evaluated using joinpoint models, adjusting for sex and age. Based on the 11,699 cases, the overall age-standardised average annual incidence rate was 45 per million. Threefold differences in the overall incidence rates were observed between the ethnic groups, ranging from 116 for whites to 37 for black Africans, and they differed by diagnostic group. Differences between the nine provinces of SA relate to the ethnic composition and prevailing socioeconomic status. The overall incidence rate declined by 1.2% per year for the whole country (p<0.01). However, the decline was mainly observed during the first few years of the study period, after which rates stabilised or increased. Diagnosis and notification of childhood cancer should improve. The differences in incidence between ethnic groups suggest the priorities for cancer control.


Making a functional diploid: from polysomic to disomic inheritance.
One little understood feature of polyploid speciation is the transition from polysomic to disomic inheritance, and much recent attention has focused on the role of pairing genes in this process. Using computer simulations we studied the effects of mutations, chromosomal inversions, chiasma, neofunctionalization, subfunctionalization and selection on the evolution of disomic inheritance in a polyploid over 10 000 generations. We show that: the evolution of pairing genes is not essential for the establishment of disomic inheritance, as genetic drift, coupled with a threshold for homologue pairing fidelity, is sufficient to explain the transition from polysomic to disomic inheritance; high rates of recombination increase the number of generations required for disomic inheritance to become established; both neofunctionalization and subfunctionalization speed up the transition to disomic inheritance. The data suggest that during polyploid species establishment, selection will favour reduced chiasma number and/or more focused distribution. The data also suggest a new role for subfunctionalization in that it can drive disomic inheritance. The evolution of subfunctionalization in genes across the genome will then act to maintain genes in syntenic blocks and may explain why such regions are so highly conserved.


Glycoalkaloids and metabolites inhibit the growth of human colon (HT29) and liver (HepG2) cancer cells.
As part of an effort to improve plant-derived foods such as potatoes, eggplants, and tomatoes, the antiproliferative activities against human colon (HT29) and liver (HepG2) cancer cells of a series of structurally related individual compounds were examined using a microculture tetrazolium (MTT) assay. The objective was to assess the roles of the carbohydrate side chain and aglycon part of Solanum glycosides in influencing inhibitory activities of these compounds. Evaluations were carried out with four concentrations each (0.1, 1, 10, and 100 microg/mL) of the the potato trisaccharide glycoalkaloids alpha-chaconine and alpha-solanine; the disaccharides beta(1)-chaconine, beta(2)-chaconine, and beta(2)-solanine; the monosaccharide gamma-chaconine and their common aglycon solanidine; the tetrasaccharide potato glycoalkaloid dehydrocommersonine; the potato aglycon demissidine; the tetrasaccharide tomato glycoalkaloid alpha-tomatine, the trisaccharide beta(1)-tomatine, the disaccharide gamma-tomatine, the monosaccharide delta-tomatine, and their common aglycon tomatidine; the eggplant glycoalkaloids solamargine and solasonine and their common aglycon solasodine; and the nonsteroidal alkaloid jervine. All compounds were active in the assay, with the glycoalkaloids being the most active and the hydrolysis products less so. The effectiveness against the liver cells was greater than against the colon cells. Potencies of alpha-tomatine and alpha-chaconine at a concentration of 1 microg/mL against the liver carcinoma cells were higher than those observed with the anticancer drugs doxorubicin and camptothecin. Because alpha-chaconine, alpha-solanine, and alpha-tomatine also inhibited normal human liver HeLa (Chang) cells, safety considerations should guide the use of these compounds as preventative or therapeutic treatments against carcinomas.


High-Density SNP-Based Association Mapping of Seed Traits in Fenugreek Reveals Homology with Clover.
Fenugreek as a self-pollinated plant is ideal for genome-wide association mapping where traits can be marked by their association with natural mutations. However, fenugreek is poorly investigated at the genomic level due to the lack of information regarding its genome. To fill this gap, we genotyped a collection of 112 genotypes with 153,881 SNPs using double digest restriction site-associated DNA sequencing. We used 38,142 polymorphic SNPs to prove the suitability of the population for association mapping. One significant SNP was associated with both seed length and seed width, and another SNP was associated with seed color. Due to the lack of a comprehensive genetic map, it is neither possible to align the newly developed markers to chromosomes nor to predict the underlying genes. Therefore, systematic targeting of those markers to homologous genomes of other legumes can overcome those problems. A BLAST search using the genomic fenugreek sequence flanking the identified SNPs showed high homology with several members of the Trifolieae tribe indicating the potential of translational approaches to improving our understanding of the fenugreek genome. Using such a comprehensively-genotyped fenugreek population is the first step towards identifying genes underlying complex traits and to underpin fenugreek marker-assisted breeding programs.


An Evolutionary Model-Based Approach To Quantify the Genetic Barrier to Drug Resistance in Fast-Evolving Viruses and Its Application to HIV-1 Subtypes and Integrase Inhibitors.
Viral pathogens causing global disease burdens are often characterized by high rates of evolutionary changes. The extensive viral diversity at baseline can shorten the time to escape from therapeutic or immune selective pressure and alter mutational pathways. The impact of genotypic background on the barrier to resistance can be difficult to capture, particularly for agents in experimental stages or that are recently approved or expanded into new patient populations. We developed an evolutionary model-based counting method to quickly quantify the population genetic potential to resistance and assess population differences. We demonstrate its applicability to HIV-1 integrase inhibitors, as their increasing use globally contrasts with limited availability of non-B subtype resistant sequence data and corresponding knowledge gap. A large sequence data set encompassing most prevailing HIV-1 subtypes and resistance-associated mutations of currently approved integrase inhibitors was investigated. A complex interplay between codon predominance, polymorphisms, and associated evolutionary costs resulted in a subtype-dependent varied genetic potential for 15 resistance mutations against integrase inhibitors. While we confirm the lower genetic barrier of subtype B for G140S, we convincingly discard a similar effect previously suggested for G140C. A supplementary analysis for HIV-1 reverse transcriptase inhibitors identified a lower genetic barrier for K65R in subtype C through differential codon usage not reported before. To aid evolutionary interpretations of genomic differences for antiviral strategies, we advanced existing counting methods with increased sensitivity to identify subtype dependencies of resistance emergence. Future applications include novel HIV-1 drug classes or vaccines, as well as other viral pathogens.


COVID-19 and the proliferation of urban networks for health security.
Recent years have witnessed cities establishing themselves as major players in addressing global issues, often taking collective action through international city networks and organizations. These networks are important, as they amplify the voices of municipal officials, who are often excluded from high-level decision-making, and can also provide a platform for officials from low- or middle-income nations to participate in higher-level political forums. The global response to the COVID-19 pandemic has included traditional public health stakeholders-including supranational organizations, international non-governmental organizations and national authorities-but has also featured mayors and city networks, in an unprecedented fashion. Existing networks without an explicit focus on health have shifted their focuses to prioritize pandemic response and several new networks have been created. These developments are significant, not only because they represent a shift in health governance and policy, but also because cities and urban networks more broadly have exhibited a nimbleness and pragmatism unmatched by higher levels of governance. These characteristics could prove beneficial for addressing the current pandemic, as well as future health issues and emergencies. Furthermore, given the relative lack of engagement with health security issues before the COVID-19 pandemic, the drastic health and economic impacts associated with it, and the demonstrable value added by strong city leadership, there are an open policy window and a compelling case for continued city engagement in health security.


Extensive genetic diversity among populations of the malaria mosquito Anopheles moucheti revealed by population genomics.
Malaria vectors are exposed to intense selective pressures due to large-scale intervention programs that are underway in most African countries. One of the current priorities is therefore to clearly assess the adaptive potential of Anopheline populations, which is critical to understand and anticipate the response mosquitoes can elicit against such adaptive challenges. The development of genomic resources that will empower robust examinations of evolutionary changes in all vectors including currently understudied species is an inevitable step toward this goal. Here we constructed double-digest Restriction Associated DNA (ddRAD) libraries and generated 6461 Single Nucleotide Polymorphisms (SNPs) that we used to explore the population structure and demographic history of wild-caught Anopheles moucheti from Cameroon. The genome-wide distribution of allelic frequencies among samples best fitted that of an old population at equilibrium, characterized by a weak genetic structure and extensive genetic diversity, presumably due to a large long term effective population size. Estimates of FST and Linkage Disequilibrium (LD) across SNPs reveal a very low genetic differentiation throughout the genome and the absence of segregating LD blocks among populations, suggesting an overall lack of local adaptation. Our study provides the first investigation of the genetic structure and diversity in An. moucheti at the genomic scale. We conclude that, despite a weak genetic structure, this species has the potential to challenge current vector control measures and other rapid anthropogenic and environmental changes thanks to its great genetic diversity.


Comparative transcriptome analysis of transcultured human skin-derived precursors (tSKPs) from adherent monolayer culture system and tSKPs-derived fibroblasts (tFBs) by RNA-Seq.
Transcultured human skin derived precursors (tSKPs) from adherent monolayer culture system have similar characteristics as traditional skin derived precursors (SKPs), making tSKPs a suitable candidate for regenerative medicine. tSKPs can differentiate into fibroblasts. However, little is known about the molecular mechanism of the transition from tSKPs to fibroblasts. Here, we compared the transcriptional profiles of human tSKPs and tSKPs-derived fibroblasts (tFBs) by RNA-Sequence aiming to determine the candidate genes and pathways involving in the differentiation process. A total of 1042 differentially expressed genes (DEGs) were identified between tSKPs and tFBs, with 490 genes up-regulated and 552 genes down-regulated. Our study showed that these DEGs were significantly enriched in tumor necrosis factor signaling pathway, focal adhesion, extracellular matrix-receptor interaction and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) signaling pathway. A further transcription factors (TFs) analysis of DEGs revealed the significantly down-expressed TFs (p21, Foxo1and Foxc1) in tFBs were mostly the downstream nodes of PI3K-Akt signaling pathway, which suggested PI3K-Akt signaling pathway might play an important role in tSKPs differentiation. The results of our study are useful for investigating the molecular mechanisms in tSKPs differentiation into tFBs, making it possible to take advantage of their potential application in regenerative medicine.


Designing and defining dynamic protein cage nanoassemblies in solution.
Central challenges in the design of large and dynamic macromolecular assemblies for synthetic biology lie in developing effective methods for testing design strategies and their outcomes, including comprehensive assessments of solution behavior. We created and validated an advanced design of a 600-kDa protein homododecamer that self-assembles into a symmetric tetrahedral cage. The monomeric unit is composed of a trimerizing apex-forming domain genetically linked to an edge-forming dimerizing domain. Enhancing the crystallographic results, high-throughput small-angle x-ray scattering (SAXS) comprehensively contrasted our modifications under diverse solution conditions. To generate a phase diagram associating structure and assembly, we developed force plots that measure dissimilarity among multiple SAXS data sets. These new tools, which provided effective feedback on experimental constructs relative to design, have general applicability in analyzing the solution behavior of heterogeneous nanosystems and have been made available as a web-based application. Specifically, our results probed the influence of solution conditions and symmetry on stability and structural adaptability, identifying the dimeric interface as the weak point in the assembly. Force plots comparing SAXS data sets further reveal more complex and controllable behavior in solution than captured by our crystal structures. These methods for objectively and comprehensively comparing SAXS profiles for systems critically affected by solvent conditions and structural heterogeneity provide an enabling technology for advancing the design and bioengineering of nanoscale biological materials.


K Locus Effects in Gray Wolves: Experimental Assessment of TLR3 Signaling and the Gene Expression Response to Canine Distemper Virus.
In North American gray wolves, black coat color is dominantly inherited via a 3 base pair coding deletion in the canine beta defensin 3 (CBD103) gene. This 3 base pair deletion, called the KB allele, was introduced through hybridization with dogs and subsequently underwent a selective sweep that increased its frequency in wild wolves. Despite apparent positive selection, KBB wolves have lower fitness than wolves with the KyB genotype, even though the 2 genotypes show no observable differences in black coat color. Thus, the KB allele is thought to have pleiotropic effects on as-yet unknown phenotypes. Given the role of skin-expressed CBD103 in innate immunity, we hypothesized that the KB allele influences the keratinocyte gene expression response to TLR3 pathway stimulation and/or infection by canine distemper virus (CDV). To test this hypothesis, we developed a panel of primary epidermal keratinocyte cell cultures from 24 wild North American gray wolves of both Kyy and KyB genotypes. In addition, we generated an immortalized Kyy line and used CRISPR/Cas9 editing to produce a KyB line on the same genetic background. We assessed the transcriptome-wide responses of wolf keratinocytes to the TLR3 agonist polyinosinic:polycytidylic acid (polyI:C), and to live CDV. K locus genotype did not predict the transcriptional response to either challenge, suggesting that variation in the gene expression response does not explain pleiotropic effects of the KB allele on fitness. This study supports the feasibility of using cell culture methods to investigate the phenotypic effects of naturally occurring genetic variation in wild mammals.


Androgens, apoE, and Alzheimer's disease.
Increasing evidence indicates that there are reductions in estrogen and androgen levels in aged men and women. These hormonal reductions might be risk factors for cognitive impairments and the development of Alzheimer's disease (AD). Aged people show improved cognition after treatments with sex steroids. Therefore, ongoing clinical AD trials have been designed to evaluate the potential benefits of estrogen therapy in women and testosterone therapy in men. Apolipoprotein E (apoE) plays an important role in the metabolism and redistribution of lipoproteins and cholesterol. The three major human apoE isoforms, apoE2, apoE3, and apoE4, differ in their effects on AD risk and pathology. Here I review various mechanisms proposed to mediate the differential effects of apoE isoforms on brain function and highlight the potential contribution of detrimental isoform-dependent effects of apoE on androgen- and androgen receptor (AR)-mediated pathways. I also discuss potential interactions of androgens with other AD-related factors.


Associations of the residential built environment with adolescent sleep outcomes.
Over 75% of US high school students obtain insufficient sleep, placing them at risk for adverse health outcomes. Identification of modifiable determinants of adolescent sleep is needed to inform prevention strategies, yet little is known about the influence of the built environment on adolescent sleep. In this prospective study, actigraphy was used to assess sleep outcomes among 110 adolescents for 14 days each in eighth and ninth grades: duration (hours/night), onset and offset, and sleeping ≥8 hours. Home addresses were linked to built environment exposures: sound levels, tree canopy cover, street density, intersection density, population density, and housing density. Mixed-effects regression estimated associations of built environment measures with sleep outcomes, adjusting for sex, race, parent education, household income, household size, grade, weeknight status, and neighborhood poverty. A 1-standard deviation (SD) increase in neighborhood sound was associated with 16 minutes later sleep onset (β = 0.28; 95% confidence interval (CI): 0.06, 0.49) and 25% lower odds of sleeping for ≥8 hours (odds ratio (OR) = 0.75, 95% CI: 0.59, 0.96). A 1-SD increase in neighborhood tree canopy was associated with 18 minutes earlier sleep onset (β = -0.31, 95% CI: -0.49, -0.13) and 10 minutes earlier sleep offset (β= -0.17, 95% CI: -0.28, -0.05). No associations were observed for density-based exposures. Higher neighborhood sound level was associated with lower odds of sufficient sleep, while higher tree canopy cover was associated with more favorable sleep timing. Neighborhood sound levels and tree canopy cover are potential targets for policies and interventions to support healthier sleep among adolescents.


[Clavicle fracture complicated by pneumothorax. Case report and literature review].
the clavicle is one of the most commonly fractured bones, accounting for up to 4-10% of all adult's fractures. These fractures are comparatively easy to manage and typically heal with routine immobilisation. a 28 year old man had direct driving trauma to the left shoulder and reported a displaced fracture of the third lateral of left clavicle and an apical pneumothorax. The pneumothorax was treated by the insertion of a chest drain under local anaesthesia. The chest drain was removed 12 days after the injury and the patient was transferred in Traumatology for specific therapy. 6 months after the accident, the clavicular fracture had united and the chest radiograph and CT were normal. most clavicular fractures result from a fall or a trauma on ipsilateral shoulder. However, the incidence of complications associated with isolated clavicle fracture, including vascular, brachial plexus, and penumothorax, are low but potentially serious. careful history and physical examination with particular attention to the neurovascular and chest examination are vital. Close inspection of the radiographs for such potential complication are mandatory in all clavicular fractures and cannot be overstated. From the analysis of international literature, we can affirm that thoracostomy and immobilization are effective to heal pneumothorax and clavicle fracture.


[Humoral immune anti-Plasmodium falciparum AMA1 and MSP1 response in two ethnic groups living in sympatry in Mali].
Fulani of Mali are known for their lower susceptibility to Plasmodium falciparum malaria than their neighbours, the Dogon, despite similar transmission conditions. However, the mechanisms underlying these differences are poorly understood, particularly those concerning antigenspecific immune responses. The Apical Membrane Antigen 1 (AMA1) and the Merozoite Surface Antigen 1 (MSP1) are two malaria vaccine candidates, which play a pivotal role during the invasion of parasites into erythrocytes, and in the case of AMA1, of hepatocytes. Therefore, we analyzed the level of anti-AMA1 and anti-MSP1 antibodies (FVO and 3D7 alleles), by using ELISA (Enzyme Linked Immuno Sorbent Assay) to investigate whether there are differences between the two ethnic groups. Our results show that the splenic rate, the level of anti-AMA1 and anti-MSP1 were significantly higher in Fulani compared to Dogon; while the parasite rate was lower in Fulani group compared to Dogon. Our results suggest that the lower susceptibility of Fulani to malaria could be due to the higher specific humoral responses against AMA1 and MSP 1 in Fulani's ethnic group compared to Dogon.


Intensification of the meridional temperature gradient in the Great Barrier Reef following the Last Glacial Maximum.
Tropical south-western Pacific temperatures are of vital importance to the Great Barrier Reef (GBR), but the role of sea surface temperatures (SSTs) in the growth of the GBR since the Last Glacial Maximum remains largely unknown. Here we present records of Sr/Ca and δ(18)O for Last Glacial Maximum and deglacial corals that show a considerably steeper meridional SST gradient than the present day in the central GBR. We find a 1-2 °C larger temperature decrease between 17° and 20°S about 20,000 to 13,000 years ago. The result is best explained by the northward expansion of cooler subtropical waters due to a weakening of the South Pacific gyre and East Australian Current. Our findings indicate that the GBR experienced substantial meridional temperature change during the last deglaciation, and serve to explain anomalous deglacial drying of northeastern Australia. Overall, the GBR developed through significant SST change and may be more resilient than previously thought.


MO-A-213AB-03: Commissioning of a Clinical Chair for Patients Treated in the Seated Position Using an Inclined Beam Line Treatment Room.
A chair, coupled to a robotic patient positioning system (PPS) was manufactured to treat an intracranial tumor in a proton incline beam-line system. Treating patients in the seated position as accurately and efficiently as a treatment table requires the essential functions of isocentric rotation and a weight-sagging-correction algorithm for positioning patients in the seated position. The chair design incorporated a down-slope arm to achieve the desired beam-line height. To overcome this limitation of only 125 degree rotation on PPS, five indexed positions of the seat-base-plate (SBP) were implemented. An in-house developed optical tracking system using a six degree-of-freedom optical camera system was used to align the treatment room coordinate system with the chair coordinate system at all SBP positions. Furthermore, this optical tracking system quantified the sagging effect due to both the height and weight of a variety of patients. The optical tracking system can measure accuracy of 0.1 degree and 0.1 mm. The SBP rotating axis was aligned within 0.1 degree to PPS rotating axis. A residual precession of chair rotation was found to be an ellipse with long axis of 2.0 mm and short axis of 1.0 mm. An additional 0.75 mm deviation occurred between rotating of SBP and PPS axes. Sagging tilt of 0.6 degree was found on the SBP for the home position for every additional 162 lbs load. This resulted in a 1.1cm shift (0.65 cm forward and 0.87 cm) for an isocenter 90 cm away from the SBP plate. Using in-house developed optical tracking system, the overall maximum displacement of treatment chair system from isocenter is within 3.0 mm with known sagging characteristics. This characterization is essential to reduce the total treatment time and limited the number of X-rays required for accurate patient alignment in the seated position.


WS6 induces both alpha and beta cell proliferation without affecting differentiation or viability.
Agents that stimulate human pancreatic beta cell proliferation are needed to improve diabetes mellitus treatment. Recently, a small molecule, WS6, was observed to stimulate human beta cell proliferation. However, little is known about its other effects on human islets. To better understand the role of WS6 as a possible beta cell regenerative therapy, we carried out in-depth phenotypic analysis of WS6-treated human islets, exploring its effects on non-beta cell proliferation, beta cell differentiation, and islet cell viability. WS6 not only stimulated beta cell proliferation in cultured human islets (in agreement with previous reports), but also human alpha cell proliferation, indicating that WS6 is not a beta cell-specific mitogen. WS6 did not change the proportion of insulin-positive beta cells or the expression of beta cell-specific transcription factors, suggesting that WS6 does not alter beta cell differentiation, and WS6 had no effect on human islet cell apoptosis or viability. In conclusion, WS6 stimulates proliferation of both human beta and alpha cells while maintaining cellular viability and the beta cell differentiated phenotype. These findings expand the literature on WS6 and support the suggestion that WS6 may help increase human islet mass needed for successful treatment of diabetes.


In vitro skin models as a tool in optimization of drug formulation.
(Trans)dermal drug therapy is gaining increasing importance in the modern drug development. To fully utilize the potential of this route, it is important to optimize the delivery of active ingredient/drug into/through the skin. The optimal carrier/vehicle can enhance the desired outcome of the therapy therefore the optimization of skin formulations is often included in the early stages of the product development. A rational approach in designing and optimizing skin formulations requires well-defined skin models, able to identify and evaluate the intrinsic properties of the formulation. Most of the current optimization relies on the use of suitable ex vivo animal/human models. However, increasing restrictions in use and handling of animals and human skin stimulated the search for suitable artificial skin models. This review attempts to provide an unbiased overview of the most commonly used models, with emphasis on their limitations and advantages. The choice of the most applicable in vitro model for the particular purpose should be based on the interplay between the availability, easiness of the use, cost and the respective limitations.


[Nutritional therapy in metabolic changes in individuals with HIV/AIDS].
To analyze the effect of nutritional treatment on metabolic changes caused by the use of antiretroviral therapy in adults with HIV/AIDS. A systematic review of literature was conducted in the PubMed, Lilacs and Cochrane databases, between 1996 and 2010, including crossover and randomized controlled clinical trials performed in adults with HIV/AIDS using antiretroviral therapy and without opportunistic diseases. The intervention of interest was oral nutritional supplementation and/or a change in lifestyle due to specific dietary treatment: dyslipidemia, insulin resistance, lipodystrophy and systemic arterial hypertension. The Jadad scale was used for a qualitative classification of articles. A total of 385 articles were found, of which seven were included. The interventions used in these studies were as follows: diet, diet and physical exercises, diet and supplementation, and only supplementation. Dyslipidemia was the outcome assessed in all studies. Studies that assessed omega-3 supplementation found a significant reduction in triglycerides. The specific diet with omega-3 supplementation showed an increase in HDL-cholesterol. Chrome nicotinate supplementation did not have an effect on dyslipidemia. Changing one's lifestyle, including diet and physical activity, significantly reduced waist circumference, lipodystrophy and systolic blood pressure. Reduction in tryglicerides with omega-3 supplementation was the nutritional intervention with the strongest scientific evidence. Prescribing a specific diet appeared to be the most adequate intervention to increase HDL-cholesterol. Inferences could not be made about the nutritional treatment of total cholesterol, LDL-cholesterol and insulin resistance. Changes in lifestyle can promote an improvement in lipodystrophy and blood pressure.


Neuropsychological effects of levetiracetam and carbamazepine in children with focal epilepsy.
To prospectively evaluate the neuropsychological effect of levetiracetam (LVT) in comparison with carbamazepine (CBZ) and its efficacy and tolerability as a monotherapy in children with focal epilepsy. A total of 121 out of 135 screened children (4-16 years) were randomly assigned to LVT or CBZ groups in a multicenter, parallel-group, open-label trial. The study's primary endpoints were defined as the end of 52 weeks of treatment, followed by analysis of changes observed in a series of follow-up neurocognitive, behavioral, and emotional function tests performed during treatment in the per protocol population. Drug efficacy and tolerability were also analyzed among the intention-to-treat (ITT) population (ClinicalTrials.gov, number NCT02208492). Eighty-one patients (41 LVT, 40 CBZ) from the randomly assigned ITT population of 121 children (57 LVT, 64 CBZ) were followed up to their last visit. No significant worsening or differences were noted between groups in neuropsychological tests, except for the Children's Depression Inventory (LVT -1.97 vs CBZ +1.43, p = 0.027, [+] improvement of function). LVT-treated patients showed an improvement (p = 0.004) in internalizing behavioral problems on the Korean Child Behavior Checklist. Seizure-free outcomes were not different between the 2 groups (CBZ 57.8% vs LVT 66.7%, p = 0.317). Neither LVT nor CBZ adversely affected neuropsychological function in pediatric patients. Both medications were considered equally safe and effective as monotherapy in children with focal epilepsy. This study provides Class II evidence that in patients with pediatric focal epilepsy, LVT and CBZ exhibit equivalent effects on neuropsychological function.


Principles and performance of tapered fiber lasers: from uniform to flared geometry.
We have studied the recently demonstrated concept of fiber lasers based on active tapered double-clad fiber (T-DCF) in copropagating and counterpropagating configurations, both theoretically and experimentally, and compared the performance to fiber lasers based on conventional cylindrical fibers in end-pumped configurations. Specific properties of T-DCFs were considered theoretically using a rate-equation model developed for tapered fibers, and a detailed comparative study was carried out experimentally. Furthermore, we have studied mode coupling effects in long adiabatic tapers due to coiling and local bending. The results allow us to conclude that, with proper fiber design, the T-DCF technology offers a high-potential alternative for bright, cost-effective fiber devices.


Roscovitine, a small molecule CDK inhibitor induces apoptosis in multidrug-resistant human multiple myeloma cells.
Small molecule inhibitors of cyclin-dependent kinases (CDKs) show high therapeutic potential against rapidly dividing cancers and malignancies, characterized by the accumulation of transformed cells due to deregulation of apoptosis, such as multiple myeloma. In the present study we addressed the possibility that pharmacological CDK inhibitors like Roscovitine (ROSC) may be effective against human multiple myeloma cells that have acquired resistance to doxorubicin (DOX). For this purpose we selected an experimental model of human multiple myeloma-sensitive (RPMI-8226s) and doxorubicin-resistant (RPMI-8226(DOX40)) cell lines. Exposure of RPMI-8826 cells to ROSC markedly increased the proportion of hypoploid cells, representing cells undergoing apoptosis, in both sensitive and resistant cells. Unlike ROSC, DOX at high dosage did not elevate the apoptosis rate in the RPMI-8226(DOX40) cell line. Our results show that ROSC has the capacity to induce apoptosis in the RPMI-8226(DOX40) cells overexpressing the P-gp glycoprotein. Since ROSC not only inhibits cell cycle-related CDKs but also negatively regulates kinases involved in the regulation of transcription, its administration to quiescent multidrug-resistant cells might be advantageous. Inhibition of transcription of pro-survival genes such as BCL2 and MCL-1 as well as destabilization of survivin seems to improve its therapeutic efficacy.


How to justify enforcing a Ulysses contract when Ulysses is competent to refuse.
Sometimes the mentally ill have sufficient mental capacity to refuse treatment competently, and others have a moral duty to respect their refusal. However, those with episodic mental disorders may wish to precommit themselves to treatment, using Ulysses contracts known as "mental health advance directives." How can health care providers justify enforcing such contracts over an agent's current, competent refusal? I argue that providers respect an agent's autonomy not retrospectively--by reference to his or her past wishes-and not merely synchronically--so that the agent gets what he or she wants right now-but diachronically and prospectively, acting so that the agent can shape his or her circumstances as the agent wishes over time, for the agent will experience the consequences of providers' actions over time. Mental health directives accomplish this, so they are a way of respecting the agent's autonomy even when providers override the agent's current competent refusal.


Epigenetic changes during hematopoietic cell granulocytic differentiation--comparative analysis of primary CD34+ cells, KG1 myeloid cells and mature neutrophils.
Epigenetic regulation is known to affect gene expression, and recent research shows that aberrant DNA methylation patterning and histone modifications may play a role in leukemogenesis. In order to highlight the co-operation of epigenetic mechanisms acting during the latter process it is important to clarify their potential as biomarkers of granulocytic differentiation. In this study we investigated epigenetic alterations in human hematopoietic cells at a distinct differentiation stages: primary hematopoietic CD34+ cells, KG1 myeloid leukemic cells, whose development is stopped at early stage of differentiation, and mature neutrophils. We focused on the epigenetic status of cell cycle regulating (p15, p16) and differentiation related (E-cadherin and RARβ) genes. We found that the methylation level in promoter regions of some of these genes was considerably higher in KG1 cells and lower in CD34+ cells and human neutrophils. As examined and evaluated by computer-assisted methods, histone H3 and H4 modifications, i.e. H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc, were similar in CD34+ cells and human mature neutrophils. By contrast, in the KG1 cells, histone H3 and H4 modifications were quite high and increased after induction of granulocytic differentiation with the HDAC inhibitor phenyl butyrate. We found the methylation status of the examined gene promoters and histone modifications to be characteristically associated with the hematopoietic cell progenitor state, induced to differentiate myeloid KG1 cells and normal blood neutrophils. This could be achieved through epigenetic regulation of E-cadherin, p15, p16 and RARβ genes expression caused by DNA methylation/demethylation, core and linker histones distribution in stem hematopoietic cells, induced to differentiation KG1 cells and mature human neutrophils, as well as the histone modifications H3K4Me3, H3K9Ac, H3K9Ac/S10Ph and H4 hyperAc in relation to hematopoietic cell differentiation to granulocyte. These findings also suggest them as potentially important biomarkers of hematopoietic cell granulocytic differentiation and could be valuable for leukemia induced differentiation therapy.


Age and response bias: evidence from the strength-based mirror effect.
Performance in episodic memory is determined both by accurate retrieval from memory and by decision processes. A substantial body of literature suggests slightly poorer episodic memory accuracy for older than younger adults; however, age-related changes in the decision mechanisms in memory have received much less attention. Response bias, the willingness to endorse an item as remembered, is an important decision factor that contributes to episodic memory performance, and therefore understanding age-related changes in response bias is critical to theoretical development. We manipulate list strength in order to investigate two aspects of response bias. First, we evaluate whether criterion placement in episodic memory differs for older and younger adults. Second, we ask whether older adults have the same degree of flexibility to adjust the criterion in response to task demands as younger adults. Participants were tested on weakly and strongly encoded lists where word frequency (Experiment 1) or similarity between targets and foils (Experiment 2) was manipulated. Both older and younger adults had higher hit rates and lower false-alarm rates for strong lists than for weak lists (i.e., a strength-based mirror effect). Older adults were more conservative (less likely to endorse an item as studied) than younger adults, and we found no evidence that older and younger adults differ in their ability to flexibly adjust their criterion based on the demands of the task.


Transmission intensity and impact of control policies on the foot and mouth epidemic in Great Britain.
The foot and mouth disease (FMD) epidemic in British livestock remains an ongoing cause for concern, with new cases still arising in previously unaffected areas. Epidemiological analyses have been vital in delivering scientific advice to government on effective control measures. Using disease, culling and census data on all livestock farms in Great Britain, we analysed the risk factors determining the spatiotemporal evolution of the epidemic and of the impact of control policies on FMD incidence. Here we show that the species mix, animal numbers and the number of distinct land parcels in a farm are central to explaining regional variation in transmission intensity. We use the parameter estimates thus obtained in a dynamical model of disease spread to show that extended culling programmes were essential for controlling the epidemic to the extent achieved, but demonstrate that the epidemic could have been substantially reduced in scale had the most efficient control measures been rigorously applied earlier.


Uterine Cervical Adenosarcoma Showing an Endophytic Growth Pattern.
Adenosarcomas are biphasic neoplasms that usually originate in the uterine corpus and comprise a benign epithelial component and a malignant stromal component. Uterine adenosarcomas typically present with abnormal genital bleeding, an enlarged uterus, and a tumor that protrudes into the endometrial cavity. These tumors rarely protrude through the cervical os and are often misdiagnosed as cervical polyps. We present the case of a patient with cervical adenosarcoma with characteristics different from those reported in previous cases. This tumor showed endophytic growth, which is rare in cervical adenosarcomas. No watery discharge or obvious genital bleeding was noted. Although the tumor measured 4 cm, vaginal bleeding was noted only once at 6 months before diagnosis and was in the form of faint brown discharge.


Treatment of pleural malignancies by photo-induction combined to systemic chemotherapy: Proof of concept on rodent lung tumors and feasibility study on porcine chest cavities.
Low-dose, Visudyne®-mediated photodynamic therapy (photo-induction) was shown to selectively enhance tumor vessel transport causing increased uptake of systemically administered chemotherapy in various tumor types grown on rodent lungs. The present experiments explore the efficacy of photo-induced vessel modulation combined to intravenous (IV) liposomal cisplatin (Lipoplatin®) on rodent lung tumors and the feasibility/toxicity of this approach in porcine chest cavities. Three groups of Fischer rats underwent orthotopic sarcoma (n = 14), mesothelioma (n = 14), or adenocarcinoma (n = 12) implantation on the left lung. Half of the animals of each group had photo-induction (0.0625 mg/kg Visudyne®, 10 J/cm(2) ) followed by IV administration of Lipoplatin® (5 mg/kg) and the other half received Lipoplatin® without photo-induction. Then, two groups of minipigs underwent intrapleural thoracoscopic (VATS) photo-induction (0.0625 mg/kg Visudyne®; 30 J/cm(2) hilum; 10 J/cm(2) apex/diaphragm) with in situ light dosimetry in combination with IV Lipoplatin® administration (5 mg/kg). Protocol I (n = 6) received Lipoplatin® immediately after light delivery and Protocol II (n = 9) 90 minutes before light delivery. Three additional animals received Lipoplatin® and VATS pleural biopsies but no photo-induction (controls). Lipoplatin® concentrations were analyzed in blood and tissues before and at regular intervals after photo-induction using inductively coupled plasma mass spectrometry. Photo-induction selectively increased Lipoplatin® uptake in all orthotopic tumors. It significantly increased the ratio of tumor to lung Lipoplatin® concentration in sarcoma (P = 0.0008) and adenocarcinoma (P = 0.01) but not in mesothelioma, compared to IV drug application alone. In minipigs, intrapleural photo-induction combined to systemic Lipoplatin® was well tolerated with no toxicity at 7 days for both treatment protocols. The pleural Lipoplatin® concentrations were not significantly different at 10 and 30 J/cm(2) locations but they were significantly higher in protocol I compared to II (2.37 ± 0.7 vs. 1.37 ± 0.7 ng/mg, P < 0.001). Visudyne®-mediated photo-induction selectively enhances the uptake of IV administered Lipoplatin® in rodent lung tumors. Intrapleural VATS photo-induction with identical treatment conditions combined to IV Lipoplatin chemotherapy is feasible and well tolerated in a porcine model. Lasers Surg. Med. 47:807-816, 2015. © 2015 Wiley Periodicals, Inc.


Systematic toxicity investigation of graphene oxide: evaluation of assay selection, cell type, exposure period and flake size.
Understanding the toxicity of nanomaterials is essential for the safe and sustainable development of new applications. This is particularly true for a nanomaterial as widely used as graphene oxide (GO), which is utilized as films for electronics, membranes for filtration, drug carriers and more. Despite this, the current literature presents conflicting results on the overall toxicity of GO. Here, the cytotoxicity of three sizes of commercially available GO was investigated on six cell lines, as values of NOAEL/LOAEL. The effectiveness of four viability assays was also evaluated. The overall toxicity of GO greatly varied between cell lines; the suspension cells showed a greater response to the GO treatment compared to the adherent cell lines. Time dependent cytotoxicity was also cell line dependent, with only one cell line demonstrating obvious dependence. The six cell lines were also tested to evaluate their response to varying GO flake sizes: the suspension/phagocytic cells showed little variation in viability, while a difference was observed for the adherent/non-phagocytic cell lines. By systematically studying the effect of dose, GO size and treatment time for the six cell lines by using commercially available GO samples, we eliminate many of the variables which may result in the conflicting reports on the cytotoxicity of GO in the literature.


Enhanced emission of encaged-OH--free Ca12(1-x)Sr12xAl14O33:0.1%Gd3+ conductive phosphors via tuning the encaged-electron concentration for low-voltage FEDs.
Encaged-OH--free Ca12(1-x)Sr12xAl14O33:0.1%Gd3+ conductive phosphors were prepared through a melt-solidification process in combination with a subsequent heat treatment. Absorption spectra showed that the maximum encaged-electron concentration was increased to 1.08 × 1021 cm-3 through optimizing the doping amount of Sr2+ (x = 0.005). Meanwhile, FTIR and Raman spectra indicated that pure Ca11.94Sr0.06Al14O33:0.1%Gd3+ conductive phosphor without encaged OH- and C22- anions was acquired. For the conductive powders heat-treated in air for different times, the encaged-electron concentrations were tuned from 1.02 × 1021 to 8.3 × 1020 cm-3. ESR, photoluminescence, and luminescence kinetics analyses indicated that the emission at 312 nm mainly originated from Gd3+ ions surrounded by encaged O2- anions, while Gd3+ ions surrounded by encaged electrons had a negative contribution to the UV emission due to the existence of an energy transfer process. Under low-voltage electron-beam excitation (3 kV), enhanced cathodoluminescence (CL) of the conductive phosphors could be achieved by tuning the encaged-electron concentrations. In particular, for the encaged-OH--free conductive phosphor, the emission intensity of the CL was about one order of magnitude higher than that of the conductive phosphor containing encaged OH- anions. Our results suggested that the encaged-OH--free conductive phosphors have potential application in low-voltage FEDs.


Environmental determinism, and not interspecific competition, drives morphological variability in Australasian warblers (Acanthizidae).
Interspecific competition is thought to play a key role in determining the coexistence of closely related species within adaptive radiations. Competition for ecological resources can lead to different outcomes from character displacement to, ultimately, competitive exclusion. Accordingly, divergent natural selection should disfavor those species that are the most similar to their competitor in resource use, thereby increasing morphological disparity. Here, we examined ecomorphological variability within an Australo-Papuan bird radiation, the Acanthizidae, which include both allopatric and sympatric complexes. In addition, we investigated whether morphological similarities between species are related to environmental factors at fine scale (foraging niche) and/or large scale (climate). Contrary to that predicted by the competition hypothesis, we did not find a significant correlation between the morphological similarities found between species and their degree of range overlap. Comparative modeling based on both a priori and data-driven identification of selective regimes suggested that foraging niche is a poor predictor of morphological variability in acanthizids. By contrast, our results indicate that climatic conditions were an important factor in the formation of morphological variation. We found a significant negative correlation between species scores for PC1 (positively associated to tarsus length and tail length) and both temperature and precipitation, whereas PC2 (positively associated to bill length and wing length) correlated positively with precipitation. In addition, we found that species inhabiting the same region are closer to each other in morphospace than to species outside that region regardless of genus to which they belong or its foraging strategy. Our results indicate that the conservative body form of acanthizids is one that can work under a wide variety of environments (an all-purpose morphology), and the observed interspecific similarity is probably driven by the common response to environment.