Human transporters associated with antigen processing (TAPs) select epitope precursor peptides for processing in the endoplasmic reticulum and presentation to T cells.
Antigen presentation by major histocompatibility complex (MHC) class I molecules requires peptide supply by the transporters associated with antigen processing (TAPs), which select substrates in a species- and, in the rat, allele-specific manner. Conflicts between TAPs and MHC preferences for COOH-terminal peptide residues in rodent cells strongly reduce the efficiency of MHC class I antigen presentation. Although human TAP is relatively permissive, some peptide ligands for human histocompatibility leukocyte antigen class I molecules are known to possess very low TAP affinities; the significance of these in vitro findings for cellular antigen presentation is not known. We studied two naturally immunodominant viral epitopes presented by HLA-A2 that display very low affinities for human TAP. Low TAP affinities preclude minimal epitope access to the endoplasmic reticulum (ER) and assembly with HLA-A2 in vitro, as well as presentation by minigene-expressing cells to cytotoxic T lymphocytes. However, NH(2)-terminally but not COOH-terminally extended epitope variants with higher TAP affinities assemble in vitro and are presented to cytotoxic T lymphocytes with high efficiency. Thus, human TAP can influence epitope selection and restrict access to the ER to epitope precursors. Analysis of TAP affinities of a panel of viral epitopes suggests that TAP selection of precursors may be a common phenomenon for HLA-A2-presented epitopes. We also analyzed HLA-A2-eluted peptides from minigene-expressing cells and show that an NH(2)-terminally extended variant with low A2 binding affinity undergoes ER processing, whereas another with high affinity is presented unmodified. Therefore, the previously reported aminopeptidase activity in the ER can also act on TAP-translocated peptides.


Characterization of a murine anti-laminin-1 monoclonal antibody (AK8) produced by immunization with mouse-derived laminin-1.
Laminin-1 is a structural glycoprotein that forms an integral part of the scaffolding of basement membranes, and plays an important role during embryonic development. We have recently demonstrated a significant association between anti-laminin1 antibodies (Abs) and reproductive failure, such as recurrent spontaneous abortions and infertility-associated endometriosis in both human and mouse studies. In the present study, we established an IgM (micro, kappa) monoclonal anti-laminin-1 Ab (AK8) by immunizing mice with mouse Engelbreth-Holm-Swarm sarcoma (EHS)-derived laminin-1. The AK8 monoclonal antibody (mAb) reacted with particular peptide sequences from the globular G domain of mouse laminin-alpha1 chain of using ELISA and Western blot techniques. The peptide tertiary structure of the epitope recognized by AK8 mAb was predicted using eight synthesized domain peptide sequences and three consensus sequences obtained by phage displayed random peptide library. Basement membranes of endometrium of pregnant mice and humans were immunostained with AK8 mAb. Thus, AK8 mAb recognized a common structure present in the G domain of the laminin-alpha1 chain in both mice and humans. The passive immunization of mice with AK8 mAb may represent a suitable animal model for anti-laminin-1 Ab-mediated reproductive failure.


rs10732516 polymorphism at the IGF2/H19 locus associates with genotype-specific effects on placental DNA methylation and birth weight of newborns conceived by assisted reproductive technology.
Assisted reproductive technology (ART) has been associated with low birth weight of fresh embryo transfer (FRESH) derived and increased birth weight of frozen embryo transfer (FET)-derived newborns. Owing to that, we focused on imprinted insulin-like growth factor 2 (IGF2)/H19 locus known to be important for normal growth. This locus is regulated by H19 imprinting control region (ICR) with seven binding sites for the methylation-sensitive zinc finger regulatory protein (CTCF). A polymorphism rs10732516 G/A in the sixth binding site for CTCF, associates with a genotype-specific trend to the DNA methylation. Due to this association, 62 couples with singleton pregnancies derived from FRESH (44 IVF/18 ICSI), 24 couples from FET (15 IVF/9 ICSI), and 157 couples with spontaneously conceived pregnancies as controls were recruited in Finland and Estonia for genotype-specific examination. DNA methylation levels at the H19 ICR, H19 DMR, and long interspersed nuclear elements in placental tissue were explored by MassARRAY EpiTYPER (n = 122). Allele-specific changes in the methylation level of H19 ICR in placental tissue (n = 26) and white blood cells (WBC, n = 8) were examined by bisulfite sequencing. Newborns' (n = 243) anthropometrics was analyzed by using international growth standards. A consistent trend of genotype-specific decreased methylation level was observed in paternal allele of rs10732516 paternal A/maternal G genotype, but not in paternal G/maternal A genotype, at H19 ICR in ART placentas. This hypomethylation was not detected in WBCs. Also genotype-specific differences in FRESH-derived newborns' birth weight and head circumference were observed (P = 0.04, P = 0.004, respectively): FRESH-derived newborns with G/G genotype were heavier (P = 0.04) and had larger head circumference (P = 0.002) compared to newborns with A/A genotype. Also, the placental weight and birth weight of controls, FRESH- and FET-derived newborns differed significantly in rs10732516 A/A genotype (P = 0.024, P = 0.006, respectively): the placentas and newborns of FET-derived pregnancies were heavier compared to FRESH-derived pregnancies (P = 0.02, P = 0.004, respectively). The observed DNA methylation changes together with the phenotypic findings suggest that rs10732516 polymorphism associates with the effects of ART in a parent-of-origin manner. Therefore, this polymorphism should be considered when the effects of environmental factors on embryonic development are studied.


Phylogenetic relationships of rock-wallabies, Petrogale (Marsupialia: Macropodidae) and their biogeographic history within Australia.
The rock-wallaby genus Petrogale comprises a group of habitat-specialist macropodids endemic to Australia. Their restriction to rocky outcrops, with infrequent interpopulation dispersal, has been suggested as the cause of their recent and rapid diversification. Molecular phylogenetic relationships within and among species of Petrogale were analysed using mitochondrial (cytochrome oxidase c subunit 1, cytochrome b, NADH dehydrogenase subunit 2) and nuclear (omega-globin intron, breast and ovarian cancer susceptibility gene) sequence data with representatives that encompassed the morphological and chromosomal variation within the genus, including for the first time both Petrogale concinna and Petrogale purpureicollis. Four distinct lineages were identified, (1) the brachyotis group, (2) Petrogale persephone, (3) Petrogalexanthopus and (4) the lateralis-penicillata group. Three of these lineages include taxa with the ancestral karyotype (2n=22). Paraphyletic relationships within the brachyotis group indicate the need for a focused phylogeographic study. There was support for P. purpureicollis being reinstated as a full species and P. concinna being placed within Petrogale rather than in the monotypic genus Peradorcas. Bayesian analyses of divergence times suggest that episodes of diversification commenced in the late Miocene-Pliocene and continued throughout the Pleistocene. Ancestral state reconstructions suggest that Petrogale originated in a mesic environment and dispersed into more arid environments, events that correlate with the timing of radiations in other arid zone vertebrate taxa across Australia.


Safety and neurological assessments after autologous transplantation of bone marrow mesenchymal stem cells in subjects with chronic spinal cord injury.
The administration of stem cells holds promise as a potential therapy for spinal cord injury (SCI). Mesenchymal stem cells have advantages for clinical applications, since they can be easily obtained, are suitable for autologous transplantation and have been previously shown to induce regeneration of the spinal cord in experimental settings. Here we evaluated the feasibility, safety and potential efficacy of autologous transplantation of mesenchymal stem cells in subjects with chronic complete SCI. We conducted a phase I, non-controlled study in 14 subjects of both genders aging between 18 to 65 years, with chronic traumatic SCI (>6 months), at thoracic or lumbar levels, classified as American Spinal Injury Association (ASIA) A - complete injury. Baseline somatosensory evoked potentials (SSEP), spinal magnetic resonance imaging (MRI) and urodynamics were assessed before and after treatment. Pain rating was performed using the McGill Pain Questionnaire and a visual analogue score scale. Bone marrow-derived mesenchymal stem cells were cultured and characterized by flow cytometry, cell differentiation assays and G-band karyotyping. Mesenchymal stem cells were injected directly into the lesion following laminectomy and durotomy. Cell transplantation was an overall safe and well-tolerated procedure. All subjects displayed variable improvements in tactile sensitivity and eight subjects developed lower limbs motor functional gains, principally in the hip flexors. Seven subjects presented sacral sparing and improved American Spinal Injury Association impairment scale (AIS) grades to B or C - incomplete injury. Nine subjects had improvements in urologic function. One subject presented changes in SSEP 3 and 6 months after mesenchymal stem cells transplantation. Statistically significant correlations between the improvements in neurological function and both injury size and level were found. Intralesional transplantation of autologous mesenchymal stem cells in subjects with chronic, complete spinal cord injury is safe, feasible, and may promote neurological improvements. ClinicalTrials.gov NCT01325103 - Registered 28 March 2011.


Technology-Based Innovations in Child Maltreatment Prevention Programs: Examples from SafeCare®
Each year, hundreds of thousands of children in the U.S. are victims of child maltreatment. Experts recommend behavioral, skill-based parent training programs as a strategy for the prevention of child abuse and neglect. These programs can be enhanced using innovative technology strategies. This paper presents a brief history of the use of technology in SafeCare®, a home visiting program shown to prevent child neglect and physical abuse, and highlights current work that takes a technology-based hybrid approach to SafeCare delivery. With this unique approach, the provider brings a tablet computer to each session, and the parent interacts with the software to receive psychoeducation and modeling of target skills. The provider and parent then work together to practice the targeted skills until mastery is achieved. Initial findings from ongoing research of both of these strategies indicate that they show potential for improving engagement and use of positive parenting skills for parents and ease of implementation for providers. Future directions for technology enhancements in SafeCare are also presented.


Electrochemical impedance spectroscopy of single Au nanorods.
We propose monochromatic dark-field imaging microscopy (DFM) to measure the non-faradaic electrochemical impedance spectroscopy (EIS) of single Au nanorods (AuNRs). DFM was utilized to monitor the plasmonic scattering of monochromatic incident light by surface-immobilized individual AuNRs. When modulating the surface potential at a certain frequency, non-faradaic charging and discharging of AuNRs altered their electron density, leading to periodical fluctuations in the scattering intensity. Analysis of the amplitude and phase of the optical intensity fluctuation as a function of modulation frequency resulted in the EIS of single AuNRs. High-frequency (>100 Hz) modulation allowed us to differentiate the intrinsic charging effect from other contributions such as the periodic migration and accumulation of counterions in the surrounding medium, because the latter occurred at a longer timescale. As a result, single nanoparticle EIS led to the surface capacitance of single AuNRs being closer to the theoretical value. Since interfacial capacitance has been proven sensitive to molecular interactions, the present work also offers a new platform for single nanoparticle sensing by measuring the single nanoparticle capacitance.


Promotion effect of Schisandra nigra on the growth of hair.
This study was conducted to evaluate the effect of Schisandra nigra, a plant native to Jeju Island, South Korea, on the promotion of hair growth. When rat vibrissa follicles were treated with 85% ethanol (EtOH) extract of S. nigra, the hair-fiber lengths of the vibrissa follicles increased significantly. In addition, after topical application of the EtOH extract of S. nigra onto the back of C57BL/6 mice every other day, anagen progression of the hair shaft was induced. Moreover, the extract increased both the expression of proliferating cell nuclear antigen (PCNA) in the bulb matrix region and the proliferation of immortalized vibrissa dermal papilla cells. In order to determine the mechanism by which S. nigra promotes hair growth, we examined its relationship with the transforming growth factor-beta2 (TGF-beta2) signal pathway, which is known to be a regulator of catagen induction. When the vibrissa follicles in the anagen phase were treated with S. nigra extract for 7 days, the expression of TGF-beta2 in the bulb matrix region was found to be lower than that of the control follicles that were expected to be in the anagen-catagen transition phase. These results suggest that S. nigra extract has the potential to promote hair growth via down regulation of TGF-beta2 and the proliferation of dermal papilla.


Integrating environmental variability to broaden the research on coral responses to future ocean conditions.
Our understanding of the response of reef-building corals to changes in their physical environment is largely based on laboratory experiments, analysis of long-term field data, and model projections. Experimental data provide unique insights into how organisms respond to variation of environmental drivers. However, an assessment of how well experimental conditions cover the breadth of environmental conditions and variability where corals live successfully is missing. Here, we compiled and analyzed a globally distributed dataset of in-situ seasonal and diurnal variability of key environmental drivers (temperature, pCO2 , and O2 ) critical for the growth and livelihood of reef-building corals. Using a meta-analysis approach, we compared the variability of environmental conditions assayed in coral experimental studies to current and projected conditions in their natural habitats. We found that annual temperature profiles projected for the end of the 21st century were characterized by distributional shifts in temperatures with warmer winters and longer warm periods in the summer, not just peak temperatures. Furthermore, short-term hourly fluctuations of temperature and pCO2 may regularly expose corals to conditions beyond the projected average increases for the end of the 21st century. Coral reef sites varied in the degree of coupling between temperature, pCO2 , and dissolved O2 , which warrants site-specific, differentiated experimental approaches depending on the local hydrography and influence of biological processes on the carbonate system and O2 availability. Our analysis highlights that a large portion of the natural environmental variability at short and long timescales is underexplored in experimental designs, which may provide a path to extend our understanding on the response of corals to global climate change.


ACC/AHA 2006 guideline update on perioperative cardiovascular evaluation for noncardiac surgery: focused update on perioperative beta-blocker therapy--a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery).
The American College of Cardiology/American Heart Association (ACC/AHA) Task Force on Practice Guidelines makes every effort to avoid any actual, potential, or perceived conflict of interest that might arise as a result of an industry relationship or personal interest of the writing committee. Specifically, all members of the writing committee, as well as peer reviewers of the document, were asked to provide disclosure statements of all such relationships that might be perceived as real or potential conflicts of interest. These statements are reviewed by the parent task force, reported orally to all members of the writing committee at each meeting, and updated and reviewed by the writing committee as changes occur. Please see Appendix 1 for author relationships with industry and Appendix 2 for peer reviewer relationships with industry. These guidelines attempt to define practices that meet the needs of most patients in most circumstances. These guideline recommendations reflect a consensus of expert opinion after a thorough review of the available, current scientific evidence and are intended to improve patient care. If these guidelines are used as the basis for regulatory/payer decisions, the ultimate goal is quality of care and serving the patient's best interests. The ultimate judgment regarding care of a particular patient must be made by the healthcare provider and patient in light of all the circumstances presented by that patient.


Microevolution of intermediary metabolism: evolutionary genetics meets metabolic biochemistry.
During the past decade, microevolution of intermediary metabolism has become an important new research focus at the interface between metabolic biochemistry and evolutionary genetics. Increasing recognition of the importance of integrative studies in evolutionary analysis, the rising interest in 'evolutionary systems biology', and the development of various 'omics' technologies have all contributed significantly to this developing interface. The present review primarily focuses on five prominent areas of recent research on pathway microevolution: lipid metabolism and life-history evolution; the electron transport system, hybrid breakdown and speciation; glycolysis, alcohol metabolism and population adaptation in Drosophila; chemostat selection in microorganisms; and anthocyanin pigment biosynthesis and flower color evolution. Some of these studies have provided a new perspective on important evolutionary topics that have not been investigated extensively from a biochemical perspective (hybrid breakdown, parallel evolution). Other studies have provided new data that augment previous biochemical information, resulting in a deeper understanding of evolutionary mechanisms (allozymes and biochemical adaptation to climate, life-history evolution, flower pigments and the genetics of adaptation). Finally, other studies have provided new insights into how the function or position of an enzyme in a pathway influences its evolutionary dynamics, in addition to providing powerful experimental models for investigations of network evolution. Microevolutionary studies of metabolic pathways will undoubtedly become increasingly important in the future because of the central importance of intermediary metabolism in organismal fitness, the wealth of biochemical data being provided by various omics technologies, and the increasing influence of integrative and systems perspectives in biology.


Cluster and propensity based approximation of a network.
The models in this article generalize current models for both correlation networks and multigraph networks. Correlation networks are widely applied in genomics research. In contrast to general networks, it is straightforward to test the statistical significance of an edge in a correlation network. It is also easy to decompose the underlying correlation matrix and generate informative network statistics such as the module eigenvector. However, correlation networks only capture the connections between numeric variables. An open question is whether one can find suitable decompositions of the similarity measures employed in constructing general networks. Multigraph networks are attractive because they support likelihood based inference. Unfortunately, it is unclear how to adjust current statistical methods to detect the clusters inherent in many data sets. Here we present an intuitive and parsimonious parametrization of a general similarity measure such as a network adjacency matrix. The cluster and propensity based approximation (CPBA) of a network not only generalizes correlation network methods but also multigraph methods. In particular, it gives rise to a novel and more realistic multigraph model that accounts for clustering and provides likelihood based tests for assessing the significance of an edge after controlling for clustering. We present a novel Majorization-Minimization (MM) algorithm for estimating the parameters of the CPBA. To illustrate the practical utility of the CPBA of a network, we apply it to gene expression data and to a bi-partite network model for diseases and disease genes from the Online Mendelian Inheritance in Man (OMIM). The CPBA of a network is theoretically appealing since a) it generalizes correlation and multigraph network methods, b) it improves likelihood based significance tests for edge counts, c) it directly models higher-order relationships between clusters, and d) it suggests novel clustering algorithms. The CPBA of a network is implemented in Fortran 95 and bundled in the freely available R package PropClust.


Carnosol: a promising anti-cancer and anti-inflammatory agent.
The Mediterranean diet and more specifically certain meats, fruits, vegetables, and olive oil found in certain parts of the Mediterranean region have been associated with a decreased cardiovascular and diabetes risk. More recently, several population based studies have observed with these lifestyle choices have reported an overall reduced risk for several cancers. One study in particular observed an inverse relationship between consumption of Mediterranean herbs such as rosemary, sage, parsley, and oregano with lung cancer. In light of these findings there is a need to explore and identify the anti-cancer properties of these medicinal herbs and to identify the phytochemicals therein. One agent in particular, carnosol, has been evaluated for anti-cancer property in prostate, breast, skin, leukemia, and colon cancer with promising results. These studies have provided evidence that carnosol targets multiple deregulated pathways associated with inflammation and cancer that include nuclear factor kappa B (NFκB), apoptotic related proteins, phosphatidylinositol-3-kinase (PI3 K)/Akt, androgen and estrogen receptors, as well as molecular targets. In addition, carnosol appears to be well tolerated in that it has a selective toxicity towards cancer cells versus non-tumorigenic cells and is well tolerated when administered to animals. This mini-review reports on the pre-clinical studies that have been performed to date with carnosol describing mechanistic, efficacy, and safety/tolerability studies as a cancer chemoprevention and anti-cancer agent.


Emotional insecurity about the community: A dynamic, within-person mediator of child adjustment in contexts of political violence.
Over 1 billion children worldwide are exposed to political violence and armed conflict. The current conclusions are qualified by limited longitudinal research testing sophisticated process-oriented explanatory models for child adjustment outcomes. In this study, consistent with a developmental psychopathology perspective emphasizing the value of process-oriented longitudinal study of child adjustment in developmental and social-ecological contexts, we tested emotional insecurity about the community as a dynamic, within-person mediating process for relations between sectarian community violence and child adjustment. Specifically, this study explored children's emotional insecurity at a person-oriented level of analysis assessed over 5 consecutive years, with child gender examined as a moderator of indirect effects between sectarian community violence and child adjustment. In the context of a five-wave longitudinal research design, participants included 928 mother-child dyads in Belfast (453 boys, 475 girls) drawn from socially deprived, ethnically homogenous areas that had experienced political violence. Youth ranged in age from 10 to 20 years and were 13.24 (SD = 1.83) years old on average at the initial time point. Greater insecurity about the community measured over multiple time points mediated relations between sectarian community violence and youth's total adjustment problems. The pathway from sectarian community violence to emotional insecurity about the community was moderated by child gender, with relations to emotional insecurity about the community stronger for girls than for boys. The results suggest that ameliorating children's insecurity about community in contexts of political violence is an important goal toward improving adolescents' well-being and adjustment. These results are discussed in terms of their translational research implications, consistent with a developmental psychopathology model for the interface between basic and intervention research.


Crystal structure of the zinc-, cobalt-, and iron-containing adenylate kinase from Desulfovibrio gigas: a novel metal-containing adenylate kinase from Gram-negative bacteria.
Adenylate kinases (AK) from Gram-negative bacteria are generally devoid of metal ions in their LID domain. However, three metal ions, zinc, cobalt, and iron, have been found in AK from Gram-negative bacteria. Crystal structures of substrate-free AK from Desulfovibrio gigas with three different metal ions (Zn(2+), Zn-AK; Co(2+), Co-AK; and Fe(2+), Fe-AK) bound in its LID domain have been determined by X-ray crystallography to resolutions 1.8, 2.0, and 3.0 Å, respectively. The zinc and iron forms of the enzyme were crystallized in space group I222, whereas the cobalt-form crystals were C2. The presence of the metals was confirmed by calculation of anomalous difference maps and by X-ray fluorescence scans. The work presented here is the first report of a structure of a metal-containing AK from a Gram-negative bacterium. The native enzyme was crystallized, and only zinc was detected in the LID domain. Co-AK and Fe-AK were obtained by overexpressing the protein in Escherichia coli. Zn-AK and Fe-AK crystallized as monomers in the asymmetric unit, whereas Co-AK crystallized as a dimer. Nevertheless, all three crystal structures are very similar to each other, with the same LID domain topology, the only change being the presence of the different metal atoms. In the absence of any substrate, the LID domain of all holoforms of AK was present in a fully open conformational state. Normal mode analysis was performed to predict fluctuations of the LID domain along the catalytic pathway.


Peptidoglycan crosslinking relaxation plays an important role in Staphylococcus aureus WalKR-dependent cell viability.
The WalKR two-component system is essential for viability of Staphylococcus aureus, a major pathogen. We have shown that WalKR acts as the master controller of peptidoglycan metabolism, yet none of the identified regulon genes explain its requirement for cell viability. Transmission electron micrographs revealed cell wall thickening and aberrant division septa in the absence of WalKR, suggesting its requirement may be linked to its role in coordinating cell wall metabolism and cell division. We therefore tested whether uncoupling autolysin gene expression from WalKR-dependent regulation could compensate for its essential nature. Uncoupled expression of genes encoding lytic transglycosylases or amidases did not restore growth to a WalKR-depleted strain. We identified only two WalKR-regulon genes whose expression restored cell viability in the absence of WalKR: lytM and ssaA. Neither of these two genes are essential under our conditions and a ΔlytM ΔssaA mutant does not present any growth defect. LytM is a glycyl-glycyl endopeptidase, hydrolyzing the pentaglycine interpeptide crossbridge, and SsaA belongs to the CHAP amidase family, members of which such as LysK and LytA have been shown to have D-alanyl-glycyl endopeptidase activity, cleaving between the crossbridge and the stem peptide. Taken together, our results strongly suggest that peptidoglycan crosslinking relaxation through crossbridge hydrolysis plays a crucial role in the essential requirement of the WalKR system for cell viability.


A new method for fibrous protein analysis illustrated by application to tubulin microtubule polymerisation and depolymerisation.
A thermostatted micro volume Couette cell has been designed to enable linear dichroism (LD) data to be collected at a range of temperatures. The cell is a development of the traditional Couette flow LD cell and includes the recent development of micro-volume LD (20-40 microL) coupled with the addition of a heating element, temperature probe and controller. This new micro volume Couette LD cell opens the way not only to the LD analysis of systems where sample volume is critical, but also for the LD analysis of temperature sensitive samples. The polymerization of the microtubule protein tubulin has been followed in a range of different conditions using the thermostatted micro volume Couette LD cell. The focusing lenses on the cell, which are required for the microvolume cell, have the side benefit of significantly reducing the light-scattering artifacts caused by the large size of tubulin microtubules. It is now possible to monitor real-time polymerization and depolymerization kinetics, and any structural rearrangements of chromophores within the polymer. In the case of tubulin, the LD spectra revealed a greater change in the orientation of tryptophan residues at approximately 290 nm during polymerization compared to other contributing chromophores-guanine, phenylalanine, and tyrosine. The improvements in instrumental design have also allowed LD spectra of tubulin to be collected down to approximately 230 nm (previous data have only been available from the near UV region), which means that some indication of protein backbone-orientation changes are now available. It was observed during this work that apparent LD intensity maxima are in fact artifacts when the high-tension voltage is high. The onset of such artifacts has been observed at much lower voltages with light-scattering fibrous proteins (including tubulin) than with nonscattering samples. Therefore, caution must be used when interpreting LD data collected with medium to high photomultiplier tube voltages.


Effects of prenatal micronutrient and early food supplementation on metabolic status of the offspring at 4.5 years of age. The MINIMat randomized trial in rural Bangladesh.
Fetal nutritional insults may alter the later metabolic phenotype. We hypothesized that early timing of prenatal food supplementation and multiple micronutrient supplementation (MMS) would favourably influence childhood metabolic phenotype. Pregnant women recruited 1 January to 31 December 2002 in Matlab, Bangladesh, were randomized into supplementation with capsules of either 30 mg of iron and 400 μg of folic acid, 60 mg of iron and 400 μg of folic acid, or MMS containing a daily allowance of 15 micronutrients, and randomized to food supplementation (608 kcal) either with early invitation (9 weeks' gestation) or usual invitation (at 20 weeks). Their children (n = 1667) were followed up at 4.5 years with assessment of biomarkers of lipid and glucose metabolism, inflammation and oxidative stress. Children in the group with early timing of food supplementation had lower cholesterol (difference -0.079 mmol/l, 95% confidence interval (CI) -0.156; -0.003), low-density lipoprotein (LDL) (difference -0.068 mmol/l, 95% CI -0.126; -0.011) and ApoB levels (difference -0.017 g/l, 95% CL -0.033; -0.001). MMS supplementation resulted in lower high-density lipoprotein (HDL) (difference -0.028 mmol/l, 95% CL -0.053; -0.002), lower glucose (difference -0.099 mmol/l, 95% CL -0.179; -0.019) and lower insulin-like growth factor 1 (IGF-1) (difference on log scale -0.141 µg/l, 95% CL -0.254; -0.028) than 60 mg iron and 400 μg folic acid. There were no effects on markers of inflammation or oxidative stress. Findings suggest that in a population where malnutrition is prevalent, nutrition interventions during pregnancy may modify the metabolic phenotype in the young child that could have consequences for later chronic disease risks.


Cell surface expression and function of an HLA class II molecule with class I domain configuration.
Recombinant major histocompatibility complex (MHC) class II molecules were expressed with extracellular polypeptide domains reorganized to form heavy (H) and light (L) chains (alpha 1-beta 1-beta 2 and alpha 2) analogous to class I. Accurate protein folding and dimerization is demonstrated by the ability of this 3+1-DR1 construct to bind class II-restricted peptides and stimulate CD4+ T cells. Cell surface expression of a functional class II molecule consisting of H and L chains supports the validity of current class II models and affirms the evolutionary relatedness of class I/II. MHC functions that differ between class I/II may be influenced by domain configuration, and the use of domain-shifted constructs will allow examination of this possibility.


Physician-Industry Interactions and Anti-Vascular Endothelial Growth Factor Use Among US Ophthalmologists.
The publication of the US Physician Payments Sunshine Act provides insight into the financial relationship between physicians and the pharmaceutical industry. This added transparency creates new opportunities of using objective data to better understand prior research that implicates pharmaceutical promotions as an important factor in a physician's decision-making process. To assess the association between reported industry payments and physician-prescribing habits by comparing the use of anti-vascular endothelial growth factor (VEGF) intravitreal injections by US ophthalmologists to the industry payments these same physicians received. This study reviews data from the Centers for Medicare & Medicaid Services (CMS) 2013 Medicare Provider Utilization and Payment Data: Physician and Other Supplier Public Use File and the CMS-sponsored August through December 2013 Open Payments program (Physician Payments Sunshine Act). Ophthalmologists who prescribe anti-VEGF injections for all indications were analyzed. Association between industry payments reportedly received and the number and type of anti-VEGF injections administered. A total of 3011 US ophthalmologists were reimbursed by CMS for 2.2 million anti-VEGF injections in 2013. Of these physicians, 38.0% reportedly received $1.3 million in industry payments for ranibizumab and aflibercept. Analysis revealed positive associations between increasing numbers of reported industry payments and total injection use (r = 0.24; 95% CI, 0.22-0.26; P < .001), aflibercept and ranibizumab injection use (r = 0.32; 95% CI, 0.29-0.34; P < .001), and percentage of injections per physician that were aflibercept or ranibizumab (r = 0.27; 95% CI, 0.25-0.29; P < .001). A smaller association was noted between greater number of industry payments and bevacizumab injection use (r = 0.07; 95% CI, 0.04-0.09; P < .001). Similar associations were found between the total dollars of reported industry payments received to injection use. Subgroup analysis further revealed that physicians receiving $1 to $25 in reported industry benefits were more likely than those not receiving industry payments to perform a greater percentage of their injections with aflibercept and ranibizumab. Among ophthalmologists who prescribe anti-VEGF medications, there is a positive association between reported pharmaceutical payments and increased use of aflibercept and ranibizumab injections. As is inherent to the design of correlation studies, this analysis cannot determine whether the payments reported caused the increased use, are a result of the increased use, or are merely associated with some other factor that causes the increased use.


Imaging findings after fascial injection of tetanus vaccine.
Adverse reactions to vaccines vary from mild to fatal. Local reactions are often due to hypersensitivity to the adjuvant substances in the vaccine. This case report aims at illustrating the imaging findings of a fascial injection of the tetanus vaccine. A 14 year-old boy, vaccinated 6 months previously presented with a mass lesion in the left deltoid area. Magnetic resonance imaging and ultrasonographic evaluations were performed and the findings were characteristic for fascial granuloma. The histopathologic examination confirmed the diagnosis. In our knowledge, this is the first case of granuloma post intrafascial injection of tetanus vaccine which was MRI and ultrasonographic evaluated and histopathologicly confirmed.


Patient Preferences Regarding Colorectal Cancer Screening: Test Features and Cost Willing to Pay Out of Pocket.
The purpose of this investigation was to evaluate whether test features would make an individual more or less likely to undergo colorectal cancer screening and how much an individual would be willing to pay out of pocket for a screening test. The methods include an administration of a survey to consecutive adult patients of a general medicine clinic. The survey consisted of Likert-scale questions assessing the patients' likelihood of choosing a screening test based on various test characteristics. Additional questions measured the patients' age, race, gender, and maximum out-of-pocket cost they would be willing to pay. Chi-square tests were used to assess the associations between the likelihood questions and the various demographic characteristics. In results, survey response rate was 88.8% (213 of 240). Respondents were 48.4% female (103 of 213), 51.6% male (110 of 213), 82.6% White (176 of 213), 11.3% African-American (24 of 213), and 6.1% other (13 of 213). Risk of internal injury and light exposure to radiation were the least desirable test features. Light sedation was the only test feature that most respondents (54.8%) indicated would make them likely or very likely to undergo a colorectal cancer screening test. The vast majority of respondents (86.8%) were willing to pay less than $200 out of pocket for a colorectal cancer screening test. There was no statistically significant difference in the responses of males and females, or in the responses of individuals of different races or different ages regarding test features, or the amount individuals were willing to pay for a screening test. To conclude, survey results suggest that patient education emphasizing the low complication rate of computed tomographic colonography (CTC), the minimal risks associated with the low-level radiation exposure resulting from CTC, and the benefits of a sedation-free test (eg, no risk of sedation-related complication and no need for a driver) may increase patient acceptance of CTC. Additionally, an out-of-pocket cost of <$200 would be preferable from the patient perspective.


Engineering T Cells with Customized Therapeutic Response Programs Using Synthetic Notch Receptors.
Redirecting T cells to attack cancer using engineered chimeric receptors provides powerful new therapeutic capabilities. However, the effectiveness of therapeutic T cells is constrained by the endogenous T cell response: certain facets of natural response programs can be toxic, whereas other responses, such as the ability to overcome tumor immunosuppression, are absent. Thus, the efficacy and safety of therapeutic cells could be improved if we could custom sculpt immune cell responses. Synthetic Notch (synNotch) receptors induce transcriptional activation in response to recognition of user-specified antigens. We show that synNotch receptors can be used to sculpt custom response programs in primary T cells: they can drive a la carte cytokine secretion profiles, biased T cell differentiation, and local delivery of non-native therapeutic payloads, such as antibodies, in response to antigen. SynNotch T cells can thus be used as a general platform to recognize and remodel local microenvironments associated with diverse diseases.


Performance comparison of full-field digital mammography to screen-film mammography in clinical practice.
Results of acceptance testing 18 full-field digital mammography systems for clinical use and of conducting annual physics surveys of 38 screen-film mammography systems were compared in terms of exposure times, mean glandular breast doses, and image quality. These evaluations were made using the same test tools on all systems, with emphasis on assessing automatic exposure control performance and image quality on both digital and screen-film systems using clinical techniques. Survey results indicated that digital mammography systems performed similarly to screen-film systems in terms of exposure times and mean glandular doses for thin to intermediate breasts, but that digital mammography systems selected shorter exposure times and lower mean glandular doses for thicker breasts. For all breast thicknesses, digital mammography systems yielded mean contrast-detail scores higher than those for screen-film systems. For all breast thicknesses, the 18 digital mammography systems demonstrated less variance in terms of exposure times, mean glandular doses, and contrast-detail scores than did the 38 screen-film systems tested. These results indicate that the clinical use of digital mammography may generally improve image quality for equal or lower breast doses, while providing tighter control on exposures and image quality than screen-film mammography.


Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits.
Regulation of the formation and rewiring of neural circuits by neuropeptides may require coordinated production of these signaling molecules and their receptors that may be established at the transcriptional level. Here, we address this hypothesis by comparing absolute expression levels of opioid peptides with their receptors, the largest neuropeptide family, and by characterizing coexpression (transcriptionally coordinated) patterns of these genes. We demonstrated that expression patterns of opioid genes highly correlate within and across functionally and anatomically different areas. Opioid peptide genes, compared with their receptor genes, are transcribed at much greater absolute levels, which suggests formation of a neuropeptide cloud that covers the receptor-expressed circuits. Surprisingly, we found that both expression levels and the proportion of opioid receptors are strongly lateralized in the spinal cord, interregional coexpression patterns are side specific, and intraregional coexpression profiles are affected differently by left- and right-side unilateral body injury. We propose that opioid genes are regulated as interconnected components of the same molecular system distributed between distinct anatomic regions. The striking feature of this system is its asymmetric coexpression patterns, which suggest side-specific regulation of selective neural circuits by opioid neurohormones.-Kononenko, O., Galatenko, V., Andersson, M., Bazov, I., Watanabe, H., Zhou, X. W., Iatsyshyna, A., Mityakina, I., Yakovleva, T., Sarkisyan, D., Ponomarev, I., Krishtal, O., Marklund, N., Tonevitsky, A., Adkins, D. L., Bakalkin, G. Intra- and interregional coregulation of opioid genes: broken symmetry in spinal circuits.


Educating adolescents about puberty: what are we missing?
Adolescents undergo significant physical and cognitive changes during their pubertal development. These changes contribute to and impact their future development. Educating adolescents at an early age about their expected development decreases the possible anxiety associated with this period of life and also helps adolescents make better choices in regards to their sexuality. In order to assess the degree of education regarding pubertal development and sexuality, we conducted a survey of late adolescents (Median age 19 years) and parents of adolescents. A total of 409 adolescents (237 females, 172 males) and 124 parents completed the survey. 14.4% of teens (36.6% of males and 2% of females) reported that no one spoke to them prior or during puberty about pubertal development or sexuality issues. Teens receiving some form of puberty/sexuality education did so at a median age of 13 for girls and 15 for boys. More than one source of information was the most common (49%) followed by mother only (20%). 85% of parents reported talking to their teens about pubertal development and sexuality. There were several differences between areas reported covered by parents but not by teens, for example 72% of parents reported talking to their teens about gender differences in growth but only 31% of teens reported being spoken to about that. Areas that are very poorly covered are breast development in boys and sexual assault/date rape in girls at 5% and 26% respectively. In summary, it appears that we continue to do a relatively poor job in educating our kids about their development and sexuality and we do it late. Boys are even less likely than girls to be talked to about many areas of pubertal development and sexuality and when that is done, it is done at a later age.


TPR proteins required for anaphase progression mediate ubiquitination of mitotic B-type cyclins in yeast.
The abundance of B-type cyclin-CDK complexes is determined by regulated synthesis and degradation of cyclin subunits. Cyclin proteolysis is required for the final exit from mitosis and for the initiation of a new cell cycle. In extracts from frog or clam eggs, degradation is accompanied by ubiquitination of cyclin. Three genes, CDC16, CDC23, and CSE1 have recently been shown to be required specifically for cyclin B proteolysis in yeast. To test whether these genes are required for cyclin ubiquitination, we prepared extracts from G1-arrested yeast cells capable of conjugating ubiquitin to the B-type cyclin Clb2. The ubiquitination activity was cell cycle regulated, required Clb2's destruction box, and was low if not absent in cdc16, cdc23, cdc27, and cse1 mutants. Furthermore all these mutants were also defective in ubiquitination of another mitotic B-type cyclin, Clb3. The Cdc16, Cdc23, and Cdc27 proteins all contain several copies of the tetratricopeptide repeat and are subunits of a complex that is required for the onset of anaphase. The finding that gene products that are required for ubiquitination of Clb2 and Clb3 are also required for cyclin proteolysis in vivo provides the best evidence so far that cyclin B is degraded via the ubiquitin pathway in living cells. Xenopus homologues of Cdc16 and Cdc27 have meanwhile been shown to be associated with a 20S particle that appears to function as a cell cycle-regulated ubiquitin-protein ligase.


Consequences of intraspecific variation in seed dispersal for plant demography, communities, evolution and global change.
As the single opportunity for plants to move, seed dispersal has an important impact on plant fitness, species distributions and patterns of biodiversity. However, models that predict dynamics such as risk of extinction, range shifts and biodiversity loss tend to rely on the mean value of parameters and rarely incorporate realistic dispersal mechanisms. By focusing on the mean population value, variation among individuals or variability caused by complex spatial and temporal dynamics is ignored. This calls for increased efforts to understand individual variation in dispersal and integrate it more explicitly into population and community models involving dispersal. However, the sources, magnitude and outcomes of intraspecific variation in dispersal are poorly characterized, limiting our understanding of the role of dispersal in mediating the dynamics of communities and their response to global change. In this manuscript, we synthesize recent research that examines the sources of individual variation in dispersal and emphasize its implications for plant fitness, populations and communities. We argue that this intraspecific variation in seed dispersal does not simply add noise to systems, but, in fact, alters dispersal processes and patterns with consequences for demography, communities, evolution and response to anthropogenic changes. We conclude with recommendations for moving this field of research forward.


Associations between sex work laws and sex workers' health: A systematic review and meta-analysis of quantitative and qualitative studies.
Sex workers are at disproportionate risk of violence and sexual and emotional ill health, harms that have been linked to the criminalisation of sex work. We synthesised evidence on the extent to which sex work laws and policing practices affect sex workers' safety, health, and access to services, and the pathways through which these effects occur. We searched bibliographic databases between 1 January 1990 and 9 May 2018 for qualitative and quantitative research involving sex workers of all genders and terms relating to legislation, police, and health. We operationalised categories of lawful and unlawful police repression of sex workers or their clients, including criminal and administrative penalties. We included quantitative studies that measured associations between policing and outcomes of violence, health, and access to services, and qualitative studies that explored related pathways. We conducted a meta-analysis to estimate the average effect of experiencing sexual/physical violence, HIV or sexually transmitted infections (STIs), and condomless sex, among individuals exposed to repressive policing compared to those unexposed. Qualitative studies were synthesised iteratively, inductively, and thematically. We reviewed 40 quantitative and 94 qualitative studies. Repressive policing of sex workers was associated with increased risk of sexual/physical violence from clients or other parties (odds ratio [OR] 2.99, 95% CI 1.96-4.57), HIV/STI (OR 1.87, 95% CI 1.60-2.19), and condomless sex (OR 1.42, 95% CI 1.03-1.94). The qualitative synthesis identified diverse forms of police violence and abuses of power, including arbitrary arrest, bribery and extortion, physical and sexual violence, failure to provide access to justice, and forced HIV testing. It showed that in contexts of criminalisation, the threat and enactment of police harassment and arrest of sex workers or their clients displaced sex workers into isolated work locations, disrupting peer support networks and service access, and limiting risk reduction opportunities. It discouraged sex workers from carrying condoms and exacerbated existing inequalities experienced by transgender, migrant, and drug-using sex workers. Evidence from decriminalised settings suggests that sex workers in these settings have greater negotiating power with clients and better access to justice. Quantitative findings were limited by high heterogeneity in the meta-analysis for some outcomes and insufficient data to conduct meta-analyses for others, as well as variable sample size and study quality. Few studies reported whether arrest was related to sex work or another offence, limiting our ability to assess the associations between sex work criminalisation and outcomes relative to other penalties or abuses of police power, and all studies were observational, prohibiting any causal inference. Few studies included trans- and cisgender male sex workers, and little evidence related to emotional health and access to healthcare beyond HIV/STI testing. Together, the qualitative and quantitative evidence demonstrate the extensive harms associated with criminalisation of sex work, including laws and enforcement targeting the sale and purchase of sex, and activities relating to sex work organisation. There is an urgent need to reform sex-work-related laws and institutional practices so as to reduce harms and barriers to the realisation of health.


Studies of the maltose transport system reveal a mechanism for coupling ATP hydrolysis to substrate translocation without direct recognition of substrate.
The ATPase activity of the maltose transporter (MalFGK(2)) is dependent on interactions with the maltose-binding protein (MBP). To determine whether direct interactions between the translocated sugar and MalFGK(2) are important for the regulation of ATP hydrolysis, we used an MBP mutant (sMBP) that is able to bind either maltose or sucrose. We observed that maltose- and sucrose-bound sMBP stimulate equal levels of MalFGK(2) ATPase activity. Therefore, the ATPase activity of MalFGK(2) is coupled to translocation of maltose solely by interactions between MalFGK(2) and MBP. For both maltose and sucrose, the ability of sMBP to stimulate the MalFGK(2) ATPase was greatly reduced compared with wild-type MBP, indicating that the mutations in sMBP have interfered with important interactions between MBP and MalFGK(2). High resolution crystal structure analysis of sMBP shows that in the closed conformation with bound sucrose, three of four mutations are buried, and the fourth causes only a minor change in the accessible surface. In contrast, in the open form of sMBP, all of the mutations are accessible, and the main chain of Tyr(62)-Gly(69) is destabilized and occupies an alternative conformation due to the W62Y mutation. On this basis, the compromised ability of sMBP to stimulate ATP hydrolysis by MalFGK(2) is most likely due to a disruption of interactions between MalFGK(2) and the open, rather than the closed, conformation of sMBP. Modeling the open sMBP structure bound to MalFGK(2) in the transition state for ATP hydrolysis points to an important site of interaction and suggests a mechanism for coupling ATP hydrolysis to substrate translocation that is independent of the exact structure of the substrate.


Modulation of somatosensory processing in dual tasks: an event-related brain potential study.
The amplitudes of the event-related brain potentials (ERPs) have been associated with the amount of attentional resources. The present study investigated whether force production type (increasing or decreasing force) in a visuomotor force tracking task modulates the ERPs elicited in a somatosensory oddball task performed simultaneously, whether stimulus-response coupling assessed by a single-trial analysis of P300 latency is modulated by the concurrent performance of the tasks, and whether dynamic visuomotor coordination rather static coordination is sensitive to the ERP modulation. In the dual-task condition, the subjects tracked a target line moving on the display with another line representing the force generated by the grip of their left hand, while executing the somatosensory oddball task with the right hand. In the oddball-only condition, the oddball task only was performed. The amplitude of the P300 elicited in the oddball task was decreased in the dual-task condition compared with the oddball-only condition, and further decreased in the force-decreasing phase compared with the increasing phase, but was not altered by the concurrently performed isometric contraction. P100, N140, reaction time (RT), and error rate were not influenced by force production type. A correlation analysis of single-trial P300 latency and RT showed that the dual-task condition produced a stronger coupling of the P300 and RT. In summary, different force production types requiring dynamic visuomotor coordination alter a modality-nonspecific late stage of somatosensory processing but have less of an effect on early stages. During the performance of the dual task, stimulus-response coupling in the somatosensory discrimination task becomes stronger to compensate for a lack of resources and/or due to snap decisions owing to sufficient resources.


Discrepant fibrinolytic response in plasma and whole blood during experimental endotoxemia in healthy volunteers.
Sepsis induces early activation of coagulation and fibrinolysis followed by late fibrinolytic shutdown and progressive endothelial damage. The aim of the present study was to investigate and compare the functional hemostatic response in whole blood and plasma during experimental human endotoxemia by the platelet function analyzer, Multiplate and by standard and modified thrombelastography (TEG). Prospective physiologic study of nine healthy male volunteers undergoing endotoxemia by means of a 4-hour infusion of E. coli lipopolysaccharide (LPS, 0.5 ng/kg/hour), with blood sampled at baseline and at 4 h and 6 h. Physiological and standard biochemical data and coagulation tests, TEG (whole blood: TEG, heparinase-TEG, Functional Fibrinogen; plasma: TEG±tissue-type plasminogen activator (tPA)) and Multiplate (TRAPtest, ADPtest, ASPItest, COLtest) were recorded. Mixed models with Tukey post hoc tests and correlations were applied. Endotoxemia induced acute SIRS with increased HR, temperature, WBC, CRP and procalcitonin and decreased blood pressure. It also induced a hemostatic response with platelet consumption and reduced APTT while INR increased (all p<0.05). Platelet aggregation decreased (all tests, p<0.05), whereas TEG whole blood clot firmness increased (G, p = 0.05). Furthermore, during endotoxemia (4 h), whole blood fibrinolysis increased (clot lysis time (CLT), p<0.001) and Functional Fibrinogen clot strength decreased (p = 0.049). After endotoxemia (6 h), whole blood fibrinolysis was reduced (CLT, p<0.05). In contrast to findings in whole blood, the plasma fibrin clot became progressively more resistant towards tPA-induced fibrinolysis at both 4 h and 6 h (p<0.001). Endotoxemia induced a hemostatic response with reduced primary but enhanced secondary hemostasis, enhanced early fibrinolysis and fibrinogen consumption followed by downregulation of fibrinolysis, with a discrepant fibrinolytic response in plasma and whole blood. The finding that blood cells are critically involved in the vasculo-fibrinolytic response to acute inflammation is important given that disturbances in the vascular system contribute significantly to morbidity and mortality in critically ill patients.


The longer the shifts for hospital nurses, the higher the levels of burnout and patient dissatisfaction.
Extended work shifts of twelve hours or longer are common and even popular with hospital staff nurses, but little is known about how such extended hours affect the care that patients receive or the well-being of nurses. Survey data from nurses in four states showed that more than 80 percent of the nurses were satisfied with scheduling practices at their hospital. However, as the proportion of hospital nurses working shifts of more than thirteen hours increased, patients' dissatisfaction with care increased. Furthermore, nurses working shifts of ten hours or longer were up to two and a half times more likely than nurses working shorter shifts to experience burnout and job dissatisfaction and to intend to leave the job. Extended shifts undermine nurses' well-being, may result in expensive job turnover, and can negatively affect patient care. Policies regulating work hours for nurses, similar to those set for resident physicians, may be warranted. Nursing leaders should also encourage workplace cultures that respect nurses' days off and vacation time, promote nurses' prompt departure at the end of a shift, and allow nurses to refuse to work overtime without retribution.


Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) shows adaptation of grass pollen composition.
MALDI time-of-flight mass spectrometry (MALDI-TOF MS) has become a widely used tool for the classification of biological samples. The complex chemical composition of pollen grains leads to highly specific, fingerprint-like mass spectra, with respect to the pollen species. Beyond the species-specific composition, the variances in pollen chemistry can be hierarchically structured, including the level of different populations, of environmental conditions or different genotypes. We demonstrate here the sensitivity of MALDI-TOF MS regarding the adaption of the chemical composition of three Poaceae (grass) pollen for different populations of parent plants by analyzing the mass spectra with partial least squares discriminant analysis (PLS-DA) and principal component analysis (PCA). Thereby, variances in species, population and specific growth conditions of the plants were observed simultaneously. In particular, the chemical pattern revealed by the MALDI spectra enabled discrimination of the different populations of one species. Specifically, the role of environmental changes and their effect on the pollen chemistry of three different grass species is discussed. Analysis of the group formation within the respective populations showed a varying influence of plant genotype on the classification, depending on the species, and permits conclusions regarding the respective rigidity or plasticity towards environmental changes.


Non-invasive neural stem cells become invasive in vitro by combined FGF2 and BMP4 signaling.
Neural stem cells (NSCs) typically show efficient self-renewal and selective differentiation. Their invasion potential, however, is not well studied. In this study, Sox2-positive NSCs from the E14.5 rat cortex were found to be non-invasive and showed only limited migration in vitro. By contrast, FGF2-expanded NSCs showed a strong migratory and invasive phenotype in response to the combination of FGF2 and BMP4. Invasive NSCs expressed Podoplanin (PDPN) and p75NGFR (Ngfr) at the plasma membrane after exposure to FGF2 and BMP4. FGF2 and BMP4 together upregulated the expression of Msx1, Snail1, Snail2, Ngfr, which are all found in neural crest (NC) cells during or after epithelial-mesenchymal transition (EMT), but not in forebrain stem cells. Invasive cells downregulated the expression of Olig2, Sox10, Egfr, Pdgfra, Gsh1/Gsx1 and Gsh2/Gsx2. Migrating and invasive NSCs had elevated expression of mRNA encoding Pax6, Tenascin C (TNC), PDPN, Hey1, SPARC, p75NGFR and Gli3. On the basis of the strongest upregulation in invasion-induced NSCs, we defined a group of five key invasion-related genes: Ngfr, Sparc, Snail1, Pdpn and Tnc. These genes were co-expressed and upregulated in seven samples of glioblastoma multiforme (GBM) compared with normal human brain controls. Induction of invasion and migration led to low expression of differentiation markers and repressed proliferation in NSCs. Our results indicate that normal forebrain stem cells have the inherent ability to adopt a glioma-like invasiveness. The results provide a novel in vitro system to study stem cell invasion and a novel glioma invasion model: tumoral abuse of the developmental dorsoventral identity regulation.


Nuclear localization of pyrrole-imidazole polyamide-fluorescein conjugates in cell culture.
A series of hairpin pyrrole-imidazole polyamide-fluorescein conjugates were synthesized and assayed for cellular localization. Thirteen cell lines, representing 11 human cancers, one human transformed kidney cell line, and one murine leukemia cell line, were treated with 5 microM polyamide-fluorescein conjugates for 10-14 h, then imaged by confocal laser scanning microscopy. A conjugate containing a beta-alanine residue at the C terminus of the polyamide moiety showed no nuclear localization, whereas an analogous compound lacking the beta-alanine residue was strongly localized in the nuclei of all cell lines tested. The localization profiles of several other conjugates suggest that pyrrole-imidazole sequence and content, dye choice and position, linker composition, and molecular weight are determinants of nuclear localization. The attachment of fluorescein to the C terminus of a hairpin polyamide results in an approximately 10-fold reduction in DNA-binding affinity, with no loss of binding specificity with reference to mismatch binding sites.


Safety and Immunogenicity of the Heterosubtypic Influenza A Vaccine MVA-NP+M1 Manufactured on the AGE1.CR.pIX Avian Cell Line.
Seasonal influenza infections have a significant global impact leading to increased health and economic burden. The efficacy of currently available seasonal influenza vaccines targeting polymorphic surface antigens has historically been suboptimal. Cellular immune responses against highly conserved Influenza A virus antigens, such as nucleoprotein (NP) and matrix protein-1 (M1), have previously been shown to be associated with protection from disease, whilst viral-vectored vaccines are an effective strategy to boost cell-mediated immunity. We have previously demonstrated that MVA encoding NP and M1 can induce potent and persistent T cell responses against influenza. In this Phase I study, we evaluated the safety and immunogenicity of MVA-NP+M1, which was newly manufactured on an immortalized cell line, in six healthy adult participants. The vaccine was well-tolerated with only mild to moderate adverse events that resolved spontaneously and were comparable to previous studies with the same vaccine manufactured in chick embryo fibroblasts. A significant increase in vaccine-specific T cell responses was detected seven days after immunization and was directed against both antigens in the vector insert. This small Phase I study supports progression of this vaccine to a Phase IIb study to assess immunogenicity and additional protective efficacy in older adults receiving licensed seasonal influenza vaccines.


Asian consensus guidelines for gastrointestinal stromal tumor: what is the same and what is different from global guidelines.
There are some disparities between the clinical practice and profiles of cancer in Asia and those in Europe & North America. In Asia, surgical oncologists still have a major role in the multidisciplinary therapy of gastrointestinal stromal tumor (GIST), whereas medical oncologists hold this status in the West. Although the incidence of clinical GIST is considered similar between the two areas, small gastric GISTs are more frequently treated by surgery in East Asia compared with Europe & North America. The diagnosis and treatment of small submucosal tumors (SMTs), including GIST, is important in Asian clinical practice guidelines for GIST. Most items of Asian and Western GIST guidelines are very similar. There are slight differences between the two guidelines in the degree of recommendation, which may come from disparities of clinical practice and available medicines. Importantly, most clinical evidence in the GIST guidelines has been established by clinical trials conducted in Western countries, and the number of clinical trials is still limited in Asia, suggesting that Asian GIST patients may have limited access to investigational drugs after standard therapy. Finally, both Asian and Western GIST guidelines are well-harmonized in some parts, and their contents may reflect the medical circumstances of each region.


Maternal depression in the intergenerational transmission of childhood maltreatment and its sequelae: Testing postpartum effects in a longitudinal birth cohort.
Mothers who have experienced childhood maltreatment are more likely to have children also exposed to maltreatment, a phenomenon known as intergenerational transmission. Factors in the perinatal period may contribute uniquely to this transmission, but timing effects have not been ascertained. Using structural equation modeling with 1,016 mothers and their 2,032 children in the Environmental Risk Longitudinal Twin Study, we tested the mediating role of postpartum depression between maternal childhood maltreatment and a cascade of negative child outcomes, specifically child exposure to maltreatment, internalizing symptoms, and externalizing symptoms: (a) adjusting for later maternal depression, (b) comparing across sex differences, and (c) examining the relative role of maltreatment subtypes. Mothers who had been maltreated as children, especially those who had experienced emotional or sexual abuse, were at increased risk for postpartum depression. In turn, postpartum depression predicted children's exposure to maltreatment, followed by emotional and behavioral problems. Indirect effects from maternal childhood maltreatment to child outcomes were robust across child sex and supported significant mediation through postpartum depression; however, this appeared to be carried by mothers' depression beyond the postpartum period. Identifying and treating postpartum depression, and preventing its recurrence, may help interrupt the intergenerational transmission of maltreatment and its sequelae.


Secukinumab provides sustained PASDAS-defined remission in psoriatic arthritis and improves health-related quality of life in patients achieving remission: 2-year results from the phase III FUTURE 2 study.
Secukinumab has demonstrated sustained improvement in the signs and symptoms of psoriatic arthritis (PsA) over 2 years in the FUTURE 2 study (NCT01752634). This post hoc analysis assessed the ability of secukinumab to achieve Psoriatic Arthritis Disease Activity Score (PASDAS)-based remission or low disease activity (LDA) through 2 years among patients with PsA in the FUTURE 2 study. PASDAS (cut-off scores: remission ≤ 1.9; LDA > 1.9 and < 3.2; Moderate Disease Activity ≥ 3.2 and < 5.4; and high disease activity [HDA] ≥ 5.4) was assessed in the overall population (tumour necrosis factor inhibitor [TNFi]-naïve and TNFi-experienced), in patients stratified by prior TNFi use and by disease duration at weeks 16, 52 and 104. The impact of secukinumab on individual PASDAS core components and on the relationship between PASDAS states and patient-reported outcomes (PROs), including physical function, health-related quality of life (HRQoL) and work productivity, were also assessed. Data for the approved doses of secukinumab (300 and 150 mg) are reported. PASDAS scores and core components were reported as observed, and PROs were analysed using mixed models for repeated measures. In the overall population, PASDAS remission and LDA were achieved in 15.6% and 22.9%, respectively, of patients treated with secukinumab 300 mg and in 15.2% and 19.2%, respectively, in the secukinumab 150 mg group versus 2.3% and 13.8%, respectively, with placebo at week 16. In the TNFi-naïve group, a higher proportion of patients achieved remission + LDA at week 16 with secukinumab 300 and 150 mg (46.2% and 42.9%, respectively) versus placebo (17.5%), with corresponding responses in TNFi-experienced patients being 22.6% and 19.4% versus 13.3%. Remission/LDA responses with secukinumab were sustained through 2 years. Patients achieving remission/LDA reported greater improvements in PROs than patients in HDA through 2 years. Secukinumab-treated patients achieved higher PASDAS-defined remissions or LDA compared with placebo at week 16, which were sustained through 2 years. Remission/LDA was achieved by both TNFi-naïve and TNFi-experienced patients treated with secukinumab, with higher rates in TNFi-naïve patients. Secukinumab-treated patients achieving remission/LDA reported significantly greater improvements in PROs, including physical function and different dimensions of health-related quality of life and work, than patients in HDA. ClinicalTrials.gov, NCT01752634 . Registered on December 19, 2012. EUDRACT, 2012-004439-22 . Registered on December 12, 2012.


The Detached Self: Investigating the Effect of Depersonalisation on Self-Bias in the Visual Remapping of Touch.
There is a growing consensus that our most fundamental sense of self is structured by the ongoing integration of sensory and motor information related to our own body. Depersonalisation (DP) is an intriguing form of altered subjective experience in which people report feelings of unreality and detachment from their sense of self. The current study used the visual remapping of touch (VRT) paradigm to explore self-bias in visual-tactile integration in non-clinical participants reporting high and low levels of depersonalisation experiences. We found that the high-DP group showed an increased overall VRT effect but a no-self-face bias, instead showing a greater VRT effect when observing the face of another person. In addition, across all participants, self-bias was negatively predicted by the occurrence of anomalous body experiences. These results indicate disrupted integration of tactile and visual representations of the bodily self in those experiencing high levels of DP and provide greater understanding of how disruptions in multisensory perception of the self may underlie the phenomenology of depersonalisation.


Associations of neighborhood problems and neighborhood social cohesion with mental health and health behaviors: the Multi-Ethnic Study of Atherosclerosis.
Few studies have investigated the specific features implicated in neighborhood-health associations. We examined associations between measures of neighborhood problems and neighborhood social cohesion with depression, smoking, drinking, and walking for exercise in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. Neighborhoods were characterized according to participant self-report and aggregated measures based on other MESA participants. Individuals living in the least problematic neighborhoods were significantly less likely to be depressed, to smoke, or to drink. Less socially cohesive neighborhoods were associated with increased depression, smoking, and not walking for exercise. Results persisted after adjusting for individual-level variables. Each measure appeared to capture distinct features of the neighborhood and associations did not differ by race/ethnicity. Results for neighborhood problems were robust to the use of aggregate measures but results for social cohesion generally were not. Future work should determine the health effect of modifying specific features of the neighborhood context.


Biallelic variants/mutations of IL1RAP in patients with steroid-sensitive nephrotic syndrome.
Nephrotic syndrome (NS) is a renal disease characterized by severe proteinuria and hypoproteinemia. Although several single-gene mutations have been associated with steroid-resistant NS, causative genes for steroid-sensitive NS (SSNS) have not been clarified. While seeking to identify causative genes associated with SSNS by whole-exome sequencing, we found compound heterozygous variants/mutations (c.524T>C; p.I175T and c.662G>A; p.R221H) of the interleukin-1 receptor accessory protein (IL1RAP) gene in two siblings with SSNS. The siblings' parents are healthy, and each parent carries a different heterozygous IL1RAP variant/mutation. Since IL1RAP is a critical subunit of the functional interleukin-1 receptor (IL-1R), we investigated the effect of these variants on IL-1R subunit function. When stimulated with IL-1β, peripheral blood mononuclear cells from the siblings with SSNS produced markedly lower levels of cytokines compared with cells from healthy family members. Moreover, IL-1R with a variant IL1RAP subunit, reconstituted on a hematopoietic cell line, had impaired binding ability and low reactivity to IL-1β. Thus, the amino acid substitutions in IL1RAP found in these NS patients are dysfunctional variants/mutations. Furthermore, in the kidney of Il1rap-/- mice, the number of myeloid-derived suppressor cells, which require IL-1β for their differentiation, was markedly reduced although these mice did not show significantly increased proteinuria in acute nephrotic injury with lipopolysaccharide treatment. Together, these results identify two IL1RAP variants/mutations in humans for the first time and suggest that IL1RAP might be a causative gene for familial NS.


Using recirculating flumes and a response surface model to investigate the role of hyporheic exchange and bacterial diversity on micropollutant half-lives.
Enhancing the understanding of the fate of wastewater-derived organic micropollutants in rivers is crucial to improve risk assessment, regulatory decision making and river management. Hyporheic exchange and sediment bacterial diversity are two factors gaining increasing importance as drivers for micropollutant degradation, but are complex to study in field experiments and usually ignored in laboratory tests aimed to estimate environmental half-lives. Flume mesocosms are useful to investigate micropollutant degradation processes, bridging the gap between the field and batch experiments. However, few studies have used flumes in this context. We present a novel experimental setup using 20 recirculating flumes and a response surface model to study the influence of hyporheic exchange and sediment bacterial diversity on half-lives of the anti-epileptic drug carbamazepine (CBZ) and the artificial sweetener acesulfame (ACS). The effect of bedform-induced hyporheic exchange was tested by three treatment levels differing in number of bedforms (0, 3 and 6). Three levels of sediment bacterial diversity were obtained by diluting sediment from the River Erpe in Berlin, Germany, with sand (1 : 10, 1 : 1000 and 1 : 100 000). Our results show that ACS half-lives were significantly influenced by sediment dilution and number of bedforms. Half-lives of CBZ were higher than ACS, and were significantly affected only by the sediment dilution variable, and thus by bacterial diversity. Our results show that (1) the flume-setup is a useful tool to study the fate of micropollutants in rivers, and that (2) higher hyporheic exchange and bacterial diversity in the sediment can increase the degradation of micropollutants in rivers.


The liver-alpha-cell axis after a mixed meal and during weight loss in type 2 diabetes.
Glucagon and amino acids may be regulated in a feedback loop called the liver-alpha-cell axis with alanine or glutamine as suggested signal molecules. We assessed this concept in individuals with type 2 diabetes in the fasting state, after ingestion of a protein-rich meal, and during weight loss. Moreover, we investigated if postprandial glucagon secretion and hepatic insulin sensitivity were related. This is a secondary analysis of a 12-week weight-loss trial (Paleolithic diet ± exercise) in 29 individuals with type 2 diabetes. Before and after the intervention, plasma glucagon and amino acids were measured in the fasting state and during 180 min after a protein-rich mixed meal. Hepatic insulin sensitivity was measured using the hyperinsulinemic-euglycemic clamp with [6,6-2H2]glucose as a tracer. The postprandial increase of plasma glucagon was associated with the postprandial increase of alanine and several other amino acids but not glutamine. In the fasted state and after the meal, glucagon levels were negatively correlated with hepatic insulin sensitivity (rS = -0.51/r = -0.58, respectively; both P < 0.05). Improved hepatic insulin sensitivity with weight loss was correlated with decreased postprandial glucagon response (r = -0.78; P < 0.001). Several amino acids, notably alanine, but not glutamine could be key signals to the alpha cell to increase glucagon secretion. Amino acids may be part of a feedback mechanism as glucagon increases endogenous glucose production and ureagenesis in the liver. Moreover, postprandial glucagon secretion seems to be tightly related to hepatic insulin sensitivity.


Phase II trial of levocetirizine with capecitabine and bevacizumab to overcome the resistance of antiangiogenic therapies in refractory metastatic colorectal cancer.
Despite the clinical success of vascular endothelial growth factor (VEGF) blockade in metastatic colorectal cancers (mCRC), resistance to anti-angiogenic drugs invariably develops. IL-8 and other cytokines have been implicated in development of resistance to anti-angiogenic therapy. Levocetirizine is a second generation H1 antihistamine with anti-inflammatory and IL-8 suppression properties. We conducted a phase II trial combining levocetirizine with capecitabine and bevacizumab to potentially overcome anti-angiogenic therapy resistance in patients with refractory mCRC. This was a single-center open-label prospective trial in refractory mCRC patients. Treatment consisted of oral capecitabine 850 mg/m2 twice daily administered as 7 days on and 7 days off, intravenous (IV) bevacizumab 5 mg/kg every 14 days and oral levocetirizine 5 mg daily. The primary end point was progression free survival (PFS) and secondary endpoints included objective response rate (ORR) and tolerability. An exploratory endpoint included correlation of PFS with cytokine levels. A sample size of 36 evaluable patients could identify a median PFS of 3.4 months at a 0.05 significance level. To examine cytokine changes related to levocetirizine treatment, patients were randomized to Arm A where levocetirizine was started 7 days after starting chemotherapy and to Arm B where levocetirizine was started 7 days prior to chemotherapy. Cytokine levels were measured at baseline and with each cycle of chemotherapy (up to three cycles). Forty-seven patients were enrolled in the trial to have 36 evaluable patients. Arm A enrolled 23 patients and Arm B enrolled 24 patients. Fifty percent of patients had progressive disease and 62% of patients had stable disease in each arm as best response. There was no demonstrable difference in PFS between the two arms (log-rank test P=0.83). Median time to progression was 3.4 months in Arm A and 3.5 months in Arm B. Median PFS in the trial was comparable to and appeared to be better than other regimens used in the refractory setting (e.g., median PFS of 1.9 months for regorafenib). Cytokine measurement with IL-8 levels did not show any correlation with progression free survival but patients with stable disease showed overall lower levels of IL-8 as compared to patients with progressive disease in the cytokine analysis.


Prevalence, determinants and spectrum of attention-deficit hyperactivity disorder (ADHD) medication of children and adolescents in Germany: results of the German Health Interview and Examination Survey (KiGGS).
To investigate the prevalence, determinants and spectrum of attention-deficit hyperactivity disorder (ADHD) medication and its associations with socioeconomic status (SES), health-related behaviour and living conditions. Observational cross-sectional study. Germany. Representative population-based sample of non-institutionalised youth aged between 0 and 17 years (n=17 450) and examined between 2003 and 2006. Prevalence and spectrum of ADHD medication (Anatomical Therapeutic Chemical (ATC) code N04BA) measured by standardised computer-assisted personal interview (CAPI) on drug use. The overall prevalence of ADHD medication (stimulants including atomoxetine) was 0.9% (95% CI 0.7% to 1.1%). Boys used these drugs (1.5%, 1.2% to 1.8%) five times more than girls 0.3% (0.2% to 0.5%). The highest prevalence rates were for boys aged 6-10 years (2.3%, 1.7% to 3.1%S) and 11-13 (2.7%, 2.0% to 3.7%). Boys from families with no immigration background used ADHD medication almost 6 times as frequently as boys with an immigration background (1.7% vs 0.3%). Multivariate analysis (binary logistic regression) showed boys (OR 5.16, 95% CI 3.15 to 8.47), 11-year-olds to 13-year-olds (2.24, 1.28 to 3.49), children in large cities (2.18, 1.13 to 4.22), children with no immigration background (3.06, 1.34 to 6.99), and children with only a good (vs excellent) parent-rated health status (1.91, 1.18 to 3.08) being more likely to be using ADHD medication. A visit to the doctor in the last month or last quarter was associated with a higher probability for ADHD medication (3.18, 1.29 to 7.95 and 3.59, 1.45 to 8.90, respectively). Results show prevalence rates of ADHD medication use for the German child and adolescent population that are considerably lower than published prevalence rates from the USA, but comparable with those of western European and Scandinavian countries. Lower use rates in rural versus urban regions may point to differential healthcare access. The inverse association of ADHD medication use with immigration status suggests potentially restricted access to healthcare services for immigrants or may reflect culture-specific differences in attitudes towards symptoms of ADHD.


Low statistical power in biomedical science: a review of three human research domains.
Studies with low statistical power increase the likelihood that a statistically significant finding represents a false positive result. We conducted a review of meta-analyses of studies investigating the association of biological, environmental or cognitive parameters with neurological, psychiatric and somatic diseases, excluding treatment studies, in order to estimate the average statistical power across these domains. Taking the effect size indicated by a meta-analysis as the best estimate of the likely true effect size, and assuming a threshold for declaring statistical significance of 5%, we found that approximately 50% of studies have statistical power in the 0-10% or 11-20% range, well below the minimum of 80% that is often considered conventional. Studies with low statistical power appear to be common in the biomedical sciences, at least in the specific subject areas captured by our search strategy. However, we also observe evidence that this depends in part on research methodology, with candidate gene studies showing very low average power and studies using cognitive/behavioural measures showing high average power. This warrants further investigation.


Commodity risk assessment of Citrus L. fruits from South Africa for Thaumatotibia leucotreta under a systems approach.
The European Commission requested to the EFSA Panel on Plant Health to evaluate a dossier from South Africa where the application of the systems approach to mitigate the risk of entry of the false codling moth, Thaumatotibia leucotreta (Lepidoptera: Tortricidae), into the EU when trading citrus fruits is explained. After collecting additional evidence from the Department of Agriculture, Land Reform and Rural Development of South Africa, and reviewing the published literature, the Panel performed an assessment on the likelihood of pest freedom for T. leucotreta on citrus fruits at the point of entry in the EU considering the proposed systems approach. An expert judgement is given on the likelihood of pest freedom following the evaluation of the risk mitigation measures on T. leucotreta, including any uncertainties. There are three options (i.e. A, B and C) within the systems approach followed in South Africa that differentiate mainly in the sampling intensity in the field and the packing house as well as in temperature conditions during shipment. Therefore, three independent elicitations were conducted, one for each option. The main uncertainties were: (1) whether sampling once per orchard is representative for subsequent harvests (within 4 weeks) from the same orchard; (2) the correct implementation of the temperature regimes during shipment; (3) the mortality rate in fruit estimated for the different temperature regimes. The Expert Knowledge Elicitation indicated with 95% certainty that 9,182 out of 10,000 pallets for option A, 8,478 out of 10,000 pallets for option B, and 9,743 out of 10,000 pallets for option C will be free from T. leucotreta. In light of the additional information provided by South Africa once the elicitations were performed, it became apparent that the setting temperature during shipment was not achieved in 12 out of 14 cases of interceptions. Therefore, there is increased uncertainty on pest freedom. The Panel identified the weaknesses associated with the risk mitigation measures in the systems approach and made recommendations that could increase its effectiveness.


Strontium-impregnated bioabsorbable composite for osteoporotic fracture fixation.
Osteoporosis impairs the bone-healing process as well as bone fracture fixation. The intervention of osteoporosis is considered to be one part of bone fracture treatment. Thus, orthopedic fixators impregnated with antiosteoporosis regimens will improve fracture fixation in osteoporotic bone. In this study, the strontium (Sr) and calcium phosphate ceramic (CPC) were mixed first and then mixed with poly(ε-caprolactone) (PCL) to fabricate a bioactive and bioabsorbable bone fixators. The prepared Sr-CPC/PCL screws were implanted into the distal femur of ovariectomized rabbits. The results showed that Sr-CPC/PCL composite had the appropriate mechanical properties, good biocompatibility, and radio-opacity. The Sr addition created a porous structure and accelerated the degradation of bone screws, but the degradation products did not acidify the surrounding environment. For osteoporotic animals, favorable osteointegration around the Sr-CPC/PCL screws was found, and the total porosity of trabecular bone was decreased under the inspections of micro-computerized tomography. Compared with PCL or CPC/PCL screw, animals which received Sr-CPC/PCL were found to have better results in terms of trabecular number, thickness, and separation. This study reveals that the Sr-impregnated bone fixator improves osseointegration in osteoporotic animals. Sr-CPC/PCL composite is a good candidate material for osteofixation in osteoporotic patients.


Systemic combinatorial peptide selection yields a non-canonical iron-mimicry mechanism for targeting tumors in a mouse model of human glioblastoma.
The management of CNS tumors is limited by the blood-brain barrier (BBB), a vascular interface that restricts the passage of most molecules from the blood into the brain. Here we show that phage particles targeted with certain ligand motifs selected in vivo from a combinatorial peptide library can cross the BBB under normal and pathological conditions. Specifically, we demonstrated that phage clones displaying an iron-mimic peptide were able to target a protein complex of transferrin and transferrin receptor (TfR) through a non-canonical allosteric binding mechanism and that this functional protein complex mediated transport of the corresponding viral particles into the normal mouse brain. We also showed that, in an orthotopic mouse model of human glioblastoma, a combination of TfR overexpression plus extended vascular permeability and ligand retention resulted in remarkable brain tumor targeting of chimeric adeno-associated virus/phage particles displaying the iron-mimic peptide and carrying a gene of interest. As a proof of concept, we delivered the HSV thymidine kinase gene for molecular-genetic imaging and targeted therapy of intracranial xenografted tumors. Finally, we established that these experimental findings might be clinically relevant by determining through human tissue microarrays that many primary astrocytic tumors strongly express TfR. Together, our combinatorial selection system and results may provide a translational avenue for the targeted detection and treatment of brain tumors.


International Union of Basic and Clinical Pharmacology CIII: Chemerin Receptors CMKLR1 (Chemerin1) and GPR1 (Chemerin2) Nomenclature, Pharmacology, and Function.
Chemerin, a chemoattractant protein and adipokine, has been identified as the endogenous ligand for a G protein-coupled receptor encoded by the gene CMKLR1 (also known as ChemR23), and as a consequence the receptor protein was renamed the chemerin receptor in 2013. Since then, chemerin has been identified as the endogenous ligand for a second G protein-coupled receptor, encoded by the gene GPR1 Therefore, the International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification recommends that the official name of the receptor protein for chemokine-like receptor 1 (CMKLR1) is chemerin receptor 1, and G protein-coupled receptor 1 is chemerin receptor 2 to follow the convention of naming the receptor protein after the endogenous ligand. Chemerin receptor 1 and chemerin receptor 2 can be abbreviated to Chemerin1 and Chemerin2, respectively. Chemerin requires C-terminal processing for activity, and human chemerin21-157 is reported to be the most active form, with peptide fragments derived from the C terminus biologically active at both receptors. Small-molecule antagonist, CCX832, selectively blocks CMKLR1, and resolvin E1 activation of CMKLR1 is discussed. Activation of both receptors by chemerin is via coupling to Gi/o, causing inhibition of adenylyl cyclase and increased Ca2+ flux. Receptors and ligand are widely expressed in humans, rats, and mice, and both receptors share ∼80% identity across these species. CMKLR1 knockout mice highlight the role of this receptor in inflammation and obesity, and similarly, GPR1 knockout mice exhibit glucose intolerance. In addition, the chemerin receptors have been implicated in cardiovascular disease, cancer, steroidogenesis, human immunodeficiency virus replication, and neurogenerative disease.


Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects.
Genetic polymorphisms in cytochrome P450 (CYP) genes can result in altered metabolic activity toward a plethora of clinically important medications. Thus, single nucleotide variants and copy number variations in CYP genes are major determinants of drug pharmacokinetics and toxicity and constitute pharmacogenetic biomarkers for drug dosing, efficacy, and safety. Strikingly, the distribution of CYP alleles differs considerably between populations with important implications for personalized drug therapy and healthcare programs. To provide a global distribution map of CYP alleles with clinical importance, we integrated whole-genome and exome sequencing data from 56,945 unrelated individuals of five major human populations. By combining this dataset with population-specific linkage information, we derive the frequencies of 176 CYP haplotypes, providing an extensive resource for major genetic determinants of drug metabolism. Furthermore, we aggregated this dataset into spectra of predicted functional variability in the respective populations and discuss the implications for population-adjusted pharmacological treatment strategies.


Depression literacy in women attending university hospital clinics in Riyadh Saudi Arabia.
Depression literacy in general population constitutes an ability to understand depression, with knowledge of disease, its risk factors and symptoms. High levels of depression literacy promote early intervention, potentially reducing related disability. This study investigated the depression literacy in women visitors to clinics of a tertiary care hospital in Riyadh, Saudi Arabia. Women of 18 and more years were surveyed during their visit to primary and other healthcare clinics of a public hospital in Riyadh. Knowledge on depression symptoms, causes and management approaches identified depression literate women scoring more than 30 points on a 42-item tool. Of the 409 participants, 65.5% were depression literate, 50% educated as college and above, 64.3% married, 50.7% housewives, 62.4% reported use of multiple information sources (range, 0-8) and had a mean age of 34.9 (standard deviation ( SD), 12.4) years. In a logistic regression model, participants scoring less than 30 for depression literacy were significantly associated with women having less than college-level education, divorced marital status and use of decreasing number of learning resources. Women with low education divorced; using fewer information sources need specific considerations by healthcare providers for assessment of depressive disorders in this setting.


Absorptive carbon nanotube electrodes: consequences of optical interference loss in thin film solar cells.
A current bottleneck in the thin film photovoltaic field is the fabrication of low cost electrodes. We demonstrate ultrasonically spray coated multiwalled carbon nanotube (CNT) layers as opaque and absorptive metal-free electrodes deposited at low temperatures and free of post-deposition treatment. The electrodes show sheet resistance as low as 3.4 Ω □(-1), comparable to evaporated metallic contacts deposited in vacuum. Organic photovoltaic devices were optically simulated, showing comparable photocurrent generation between reflective metal and absorptive CNT electrodes for photoactive layer thickness larger than 600 nm when using archetypal poly(3-hexylthiophene) (P3HT) : (6,6)-phenyl C61-butyric acid methyl ester (PCBM) cells. Fabricated devices clearly show that the absorptive CNT electrodes display comparable performance to solution processed and spray coated Ag nanoparticle devices. Additionally, other candidate absorber materials for thin film photovoltaics were simulated with absorptive contacts, elucidating device design in the absence of optical interference and reflection.


Realized reproductive success of polygynous red-winged blackbirds revealed by DNA markers.
Hypervariable genetic markers, including a novel locus-specific marker detected by a mouse major histocompatibility complex probe, reveal that multiple paternity is common in families of polygynous red-winged blackbirds (Agelaius phoeniceus). Almost half of all nests contained at least one chick resulting from an extra-pair fertilization, usually by a neighboring male. Genetically based measures of reproductive success show that individual males realize more than 20% of their overall success from extra-pair fertilizations, on average, and that this form of mating behavior confounds traditional measures of male success. The importance of alternative reproductive tactics in a polygynous bird is quantified, and the results challenge previous explanations for the evolution of avian polygny.