A 3'UTR polymorphism modulates mRNA stability of the oncogene and drug target Polo-like Kinase 1.
The Polo-like Kinase 1 (PLK1) protein regulates cell cycle progression and is overexpressed in many malignant tissues. Overexpression is associated with poor prognosis in several cancer entities, whereby expression of PLK1 shows high inter-individual variability. Although PLK1 is extensively studied, not much is known about the genetic variability of the PLK1 gene. The function of PLK1 and the expression of the corresponding gene could be influenced by genomic variations. Hence, we investigated the gene for functional polymorphisms. Such polymorphisms could be useful to investigate whether PLK1 alters the risk for and the course of cancer and they could have an impact on the response to PLK1 inhibitors. The coding region, the 5' and 3'UTRs and the regulatory regions of PLK1 were systematically sequenced. We determined the allele frequencies and genotype distributions of putatively functional SNPs in 120 Caucasians and analyzed the linkage and haplotype structure using Haploview. The functional analysis included electrophoretic mobility shift assay (EMSA) for detected variants of the silencer and promoter regions and reporter assays for a 3'UTR polymorphism. Four putatively functional polymorphisms were detected and further analyzed, one in the silencer region (rs57973275), one in the core promoter region (rs16972787), one in intron 3 (rs40076) and one polymorphism in the 3'untranslated region (3'UTR) of PLK1 (rs27770). Alleles of rs27770 display different secondary mRNA structures and showed a distinct allele-dependent difference in mRNA stability with a significantly higher reporter activity of the A allele (p < 0.01). The present study provides evidence that at least one genomic variant of PLK1 has functional properties and influences expression of PLK1. This suggests polymorphisms of the PLK1 gene as an interesting target for further studies that might affect cancer risk, tumor progression as well as the response to PLK1 inhibitors.


Testing for Hereditary Risk of Ovarian Cancer.
BACKGROUND: Approximately one out of every 10 ovarian cancers is caused by inherited mutations in identified genes. The characterization of hereditary ovarian cancer as an autosomal dominant disorder of specific gene mutations is more specific and useful than descriptive clinical syndromes such as "Lynch II," "site-specific ovarian cancer," or "breast-ovarian cancer." METHODS: The author reviewed recent studies of the biology, epidemiology, and medical management of hereditary ovarian cancer risk. RESULTS: Most hereditary ovarian cancer is attributable to two genes, BRCA1 and BRCA2, with other genes accounting for a smaller fraction. Women who inherit a mutation in any of these genes are far more likely than the general population to develop an epithelial malignancy of the ovary. Appropriate evaluation of family history can identify women most likely to have hereditary cancer risk, and genetic testing can definitively identify women with germline mutations that place them and their family at increased risk of ovarian cancer. CONCLUSIONS: Hereditary risk assessment, including genetic testing, can enhance medical management when used appropriately and should be accompanied by patient education and counseling.


Effects of deoxynucleosides on cultured human leukemia cell growth and deoxynucleotide pools.
We investigated the mechanism of cell growth inhibition caused by the deoxyribonucleosides thymidine (dThd), deoxyguanosine (dGuo), deoxyadenosine (dAdo), and deoxycytidine (dCyd). Growth of the cultured human leukemic cells HL-60 and K-562 was measured by cloning in soft agar. Of the deoxyribonucleosides, dGuo was the most potent cell growth inhibitor; however, the potency of added dAdo was probably attenuated by the presence of adenosine deaminase in the tissue culture growth medium. The concentrations of nucleoside causing 50% inhibition of HL-60 cloning were: dCyd, greater than 10,000 microM; dAdo, 500 microM; dThd, 5,000 microM; and dGuo, 80 microM. For K-562 cloning, the concentrations causing 50% inhibition of cloning were dCyd, greater 10,000 microM; dAdo, 1,600 microM; dThd, 880 microM;' and dGuo, 100 microM. Measurement of deoxycytidine 5'-triphosphate (dCTP) pool size in HL-60 cells following incubation with 750 microM deoxyribonucleosides revealed that dGuo caused the greatest reduction of dCTP pools, both in early (passage 10)- and late (passage 71)-passage-derived HL-60 cell cultures (35 and 19% of control, respectively), compared to dThd (61 and 26% of control, respectively) and dAdo (39% of control of HL-60 passage 10). In K-562 cells, reductions in dCTP pool size caused by dAdo, dThd, and dGuo were 68, 46, and 35% of control, respectively. Incorporation of [3H]dCyd into DNA of HL-60 and K-562 cells was enhanced by dThd and dGuo, but the degree of enhancement was greater for dThd than for dGuo. Despite its effect in reducing HL-60 dCTP pool size, dAdo failed to enhance [3H]dCyd incorporation in either HL-60 or K-562 cells. Addition of dCyd to the cultures could only partially rescue the inhibition of HL-60 cloning caused by dThd or dGuo, suggesting that inhibition of cytidine 5'-diphosphate reduction by ribonucleotide reductase is not the only mechanism whereby these nucleosides inhibit leukemic cell cloning. These data suggest that, in addition to inhibiting de novo dCTP production via ribonucleotide reductase, these nucleosides may affect other processes in the salvage pathway such as cellular uptake and phosphorylation or the DNA polymerase reaction itself.


The efficacy, effectiveness, and immunogenicity of influenza vaccines in Africa: a systematic review.
The burden of influenza in Africa is substantial and underappreciated. Although surveillance has increased, the medical community's understanding of seasonal influenza vaccine performance remains limited. We did a systematic review, using PRISMA guidelines (PROSPERO CRD42017058107), on the efficacy, effectiveness, and immunogenicity of influenza vaccines in populations within Africa with the aim of identifying key data gaps to help direct future research. We searched Embase, MEDLINE, Global Health database, and Web of Science for published studies from database inception to May 9, 2018. Unpublished studies were identified by searching ClinicalTrials.gov and the Pan-African Clinical Trial Registry, and by contacting experts within the field. Human studies that reported influenza vaccine immunogenicity, effectiveness, and efficacy were included. 1746 articles were assessed and 23 articles were included. Only three of the 23 studies were of high quality and many studies were underpowered. All 23 studies came from only six African countries (16 from South Africa), highlighting the need for data from a broader range of African populations. The majority of studies focused on effectiveness or efficacy against laboratory supported influenza with limited data for severe outcomes. Several factors known to interfere with influenza immunisation, such as malaria, HIV, and malnutrition were under-represented in this Review and require further study. Substantial gaps exist in our understanding of influenza vaccine performance across all WHO high-risk groups in Africa. Filling these knowledge gaps is vital to guide future influenza vaccine policies.


Impaired presynaptic function and elimination of synapses at premature stages during postnatal development of the cerebellum in the absence of CALEB (CSPG5/neuroglycan C).
Chicken acidic leucine-rich EGF-like domain-containing brain protein (CALEB), also known as chondroitin sulfate proteoglycan (CSPG)5 or neuroglycan C, is a neural chondroitin sulfate-containing and epidermal growth factor (EGF)-domain-containing transmembrane protein that is implicated in synaptic maturation. Here, we studied the role of CALEB within the developing cerebellum. Adult CALEB-deficient mice displayed impaired motor coordination in Rota-Rod experiments. Analysis of the neuronal connectivity of Purkinje cells by patch-clamp recordings demonstrated impairments of presynaptic maturation of inhibitory synapses. GABAergic synapses on Purkinje cells revealed decreased evoked amplitudes, altered paired-pulse facilitation and reduced depression after repetitive stimulation at early postnatal but not at mature stages. Furthermore, the elimination of supernumerary climbing fiber synapses on Purkinje cells was found to occur at earlier developmental stages in the absence of CALEB. For example, at postnatal day 8 in wild-type mice, 54% of Purkinje cells had three or more climbing fiber synapses in contrast to mutants where this number was decreased to less than 25%. The basic properties of the climbing fiber Purkinje cell synapse remained unaffected. Using Sholl analysis of dye-injected Purkinje cells we revealed that the branching pattern of the dendritic tree of Purkinje cells was not impaired in CALEB-deficient mice. The alterations observed by patch-clamp recordings correlated with a specific pattern and timing of expression of CALEB in Purkinje cells, i.e. it is dynamically regulated during development from a high chondroitin sulfate-containing form to a non-chondroitin sulfate-containing form. Thus, our results demonstrated an involvement of CALEB in the presynaptic differentiation of cerebellar GABAergic synapses and revealed a new role for CALEB in synapse elimination in Purkinje cells.


Re-examination of the local control by nerve growth factor of the outgrowth of neurites in PC12D cells.
We have examined the local control by nerve growth factor (NGF) of the outgrowth of neurites from clonal cells, PC12D, a subline whose phenotype resembles that of the parent PC12 cell line in the NGF-primed state. We show here that (i) the outgrowth of neurites, and their survival can be induced by NGF in enucleated PC12D cells (ii) individual neurites of a single 'giant cell', produced by cell fusion of PC12D cells, can respond independently to the NGF in the local environment, (iii) dissected neurites from giant cells survive for longer in medium that contains NGF than in medium that does not, (iv) in PC12D cells, the rapid formation of ruffles in response to NGF, which appears to be based on increased cell-substratum adhesion, leads to the subsequent formation of neurites, and (v) upon addition of NGF, the movement of short processes displaces polylysine-coated beads in the vicinity of neurites. These observations suggest that the NGF-dependent maintenance or extension of neurites might be controlled within the neurites themselves and might not require the direct involvement of the cell body, even in PC12 cells. It seems possible that any NGF-induced changes that promote an increase in cell-substratum adhesion might be responsible for the initiation and elongation of neurites. It also seems possible that the growth of neurites towards a source of NGF might be based on repeated rounds of extension and retraction of filopodia and neurites in a manner that depends on the concentration of NGF.


Identification of a potential biomarker for FABP4 inhibition: the power of lipidomics in preclinical drug testing.
The fatty acid binding protein 4 (FABP4) belongs to the family of lipid chaperones that control intracellular fluxes and compartmentalization of their respective ligands (e.g., fatty acids). FABP4, which is almost exclusively expressed in adipocytes and macrophages, contributes to the development of insulin resistance and atherosclerosis in mice. Lack of FABP4 protects against the development of insulin resistance associated with genetic or diet-induced obesity in mice. Furthermore, total or macrophage-specific FABP4 deficiency is protective against atherosclerosis in apolipoprotein E-deficient mice. The FABP4 small-molecule inhibitor BMS309403 has demonstrated efficacy in mouse models for type 2 diabetes mellitus and atherosclerosis, resembling phenotypes of mice with FABP4 deficiency. However, despite the therapeutically attractive long-term effects of FABP4 inhibition, an acute biomarker for drug action is lacking. The authors applied mass spectrometry lipidomics analysis to in vitro and in vivo (plasma and adipose tissue) samples upon inhibitor treatment. They report the identification of a potential biomarker for acute in vivo FABP4 inhibition that is applicable for further investigations and can be implemented in simple and fast-flow injection mass spectrometry assays. In addition, this approach can be considered a proof-of-principle study that can be applied to other lipid-pathway targeting mechanisms.


Kinetic isotope effects in cycloreversion of rhenium (V) diolates.
Cycloreversion of 4-methoxystyrene from the corresponding Tp'Re(O)(diolato) complex (Tp' = hydrido-tris-(3,5-dimethylpyrazolyl)borate) was measured competitively for various isotopomers at 103 degrees C. Primary ((12)C/(13)C) and secondary ((1)H/(2)H) kinetic isotope effects were determined. The primary KIEs were k(12C)/k(13C) = 1.041 +/- 0.005 at the alpha position and 1.013 +/- 0.006 at the beta position. Secondary KIEs were k(H)/k(D) = 1.076 +/- 0.005 at the alpha position and 1.017 +/- 0.005 at the beta position. Computational modeling (B3LYP/LACVP+) located a transition state for concerted cycloreversion of styrene from TpRe(O)(OCH(2)CHPh) exhibiting dramatically different C-O bond lengths. A Hammett study on cycloreversions of substituted styrenes from a series of Tp'Re(O)(diolato) showed dichotomous behavior for electron donors and electron-withdrawing groups as substituents: rho = -0.65 for electron donors, but rho = +1.13 for electron-withdrawing groups. The data are considered in light of various mechanistic proposals. While the extrusion of 4-methoxystyrene is concluded to be a highly asynchronous concerted reaction, the Hammett study reflects a likelihood that multiple reaction mechanisms are involved.


Integrated temporal regulation of the photorespiratory pathway. Circadian regulation of two Arabidopsis genes encoding serine hydroxymethyltransferase.
The photorespiratory pathway is comprised of enzymes localized within three distinct cellular compartments: chloroplasts, peroxisomes, and mitochondria. Photorespiratory enzymes are encoded by nuclear genes, translated in the cytosol, and targeted into these distinct subcellular compartments. One likely means by which to regulate the expression of the genes encoding photorespiratory enzymes is coordinated temporal control. We have previously shown in Arabidopsis that a circadian clock regulates the expression of the nuclear genes encoding both chloroplastic (Rubisco small subunit and Rubisco activase) and peroxisomal (catalase) components of the photorespiratory pathway. To determine whether a circadian clock also regulates the expression of genes encoding mitochondrial components of the photorespiratory pathway, we characterized a family of Arabidopsis serine hydroxymethyltransferase (SHM) genes. We examined mRNA accumulation for two of these family members, including one probable photorespiratory gene (SHM1) and a second gene expressed maximally in roots (SHM4), and show that both exhibit circadian oscillations in mRNA abundance that are in phase with those described for other photorespiratory genes. In addition, we show that SHM1 mRNA accumulates in light-grown seedlings, although this response is probably an indirect consequence of the induction of photosynthesis and photorespiration by illumination.


Learning-based local-to-global landmark annotation for automatic 3D cephalometry.
The annotation of three-dimensional (3D) cephalometric landmarks in 3D computerized tomography (CT) has become an essential part of cephalometric analysis, which is used for diagnosis, surgical planning, and treatment evaluation. The automation of 3D landmarking with high-precision remains challenging due to the limited availability of training data and the high computational burden. This paper addresses these challenges by proposing a hierarchical deep-learning method consisting of four stages: 1) a basic landmark annotator for 3D skull pose normalization, 2) a deep-learning-based coarse-to-fine landmark annotator on the midsagittal plane, 3) a low-dimensional representation of the total number of landmarks using variational autoencoder (VAE), and 4) a local-to-global landmark annotator. The implementation of the VAE allows two-dimensional-image-based 3D morphological feature learning and similarity/dissimilarity representation learning of the concatenated vectors of cephalometric landmarks. The proposed method achieves an average 3D point-to-point error of 3.63 mm for 93 cephalometric landmarks using a small number of training CT datasets. Notably, the VAE captures variations of craniofacial structural characteristics.


Methylation of cytosine at C5 in a CpG sequence context causes a conformational switch of a benzo[a]pyrene diol epoxide-N2-guanine adduct in DNA from a minor groove alignment to intercalation with base displacement.
It is well known that CpG dinucleotide steps in DNA, which are highly methylated at the 5-position of cytosine (meC) in human tissues, exhibit a disproportionate number of mutations within certain codons of the p53 gene. There is ample published evidence indicating that the reactivity of guanine with anti-B[a]PDE (a metabolite of the environmental carcinogen benzo[a]pyrene) at CpG mutation hot spots is enhanced by the methylation of the cytosine residue flanking the target guanine residue on the 5'-side. In this work we demonstrate that such a methylation can also dramatically affect the conformational characteristics of an adduct derived from the reaction of one of the two enantiomers of anti-B[a]PDE with the exocyclic amino group of guanine ([BP]G adduct). A detailed NMR study indicates that the 10R (-)-trans-anti-[BP]G adduct undergoes a transition from a minor groove-binding alignment of the aromatic BP ring system in the unmethylated C-[BP]G sequence context, to an intercalative BP alignment with a concomitant displacement of the modified guanine residue into the minor groove in the methylated meC-[BP]G sequence context. By contrast, a minor groove-binding alignment was observed for the stereoisomeric 10S (+)-trans-anti-[BP]G adduct in both the C-[BP]G and meC-[BP]G sequence contexts. This remarkable conformational switch resulting from the presence of a single methyl group at the 5-position of the cytosine residue flanking the lesion on the 5'-side, is attributed to the hydrophobic effect of the methyl group that can stabilize intercalated adduct conformations in an adduct stereochemistry-dependent manner. Such conformational differences in methylated and unmethylated CpG sequences may be significant because of potential alterations in the cellular processing of the [BP]G adducts by DNA transcription, replication, and repair enzymes.


[Mechanisms of nephrotoxic action of immunodepressants, calcineurine inhibitors].
The use of immunodepressants in the medical practice provided tens of thousands of favourable outcomes of the liver, kidney or heart transplantation and significant success in the treatment of a number of autoimmune diseases. Calcineurine inhibitors (cyclosporine A and tacrolimus) provoke a number of adverse reactions. Among them nephrotoxicity is clinically most dangerous. Complex estimation of the immunological and biochemical indices in the treatment with calcineurine inhibitors is an important precondition for increasing the efficacy of immunodepressive therapy and decreasing the frequency and level of the adverse reactions.


Kinetic modeling of ethane pyrolysis at high conversion.
The primary objective of this study is to develop an improved first-principle-based mechanism that describes the molecular weight growth kinetics observed during ethane pyrolysis. A proper characterization of the kinetics of ethane pyrolysis is a prerequisite for any analysis of hydrocarbon pyrolysis and oxidation. Flow reactor experiments were performed with ~50/50 ethane/nitrogen mixtures with temperatures ranging from 550 to 850 °C at an absolute pressure of ~0.8 atm and a residence time of ~5 s. These conditions result in ethane conversions ranging from virtually no reaction to ~90%. Comparisons of predictions using our original mechanism to these data yielded very satisfactory results in terms of the temperature dependence of ethane conversion and prediction of the major products ethylene and hydrogen. However, there were discrepancies in some of the minor species concentrations that are involved in the molecular weight growth kinetics. We performed a series of CBS-QB3 analyses for the C(3)H(7), C(4)H(7), and C(4)H(9) potential energy surfaces to better characterize the radical addition reactions that lead to molecular weight growth. We also extended a published C(6)H(9) PES to include addition of vinyl to butadiene. The results were then used to calculate pressure-dependent rate constants for the multiple reaction pathways of these addition reactions. Inclusion of the unadjusted rate constants resulting from these analyses in the mechanism significantly improved the description of several of the species involved in molecular weight growth kinetics. We compare the predictions of this improved model to those obtained with a consensus model recently published as well as to ethane steam cracking data. We find that a particularly important reaction is that of vinyl addition to butadiene. Another important observation is that several radical addition reactions are partially equilibrated. Not only does this mean that reliable thermodynamic parameters are essential for an accurate model, but also that the reaction set describing molecular weight growth chemistry must include a final product that is sufficiently stable to shift the equilibrium toward this product despite the decrease in entropy that accompanies molecular weight growth. Another reaction, H addition to olefins, was found to inhibit molecular weight growth by leading to the production of a lower olefin plus methyl radicals.


Isolation of Vibrio cholera El Tor Inaba From Lemna minor and Eichhornia crassipens Roots in Veracruz, Mexico.
During epidemic periods, the strain Vibrio cholera El Tor has been isolated from the aquatic macrophyte roots of Eichhornia crassipens and Lemna minor, suggesting that aquatic plants could be environmental reservoirs through either a non-specific association or a commensalism relationship. Therefore, it is important to understand V. cholera reservoirs in order to establish prevention strategies against this pathogen. Our interest was to determine whether V. cholera could be isolated and typified from L. minor and E. crassipens roots. From 2004 to 2005, plants were collected from various ecological niches and the roots were used to isolate V. cholera. Standard bacteriological, biochemical and serological tests were used for its typification. In five out of the nine ecological niches explored, we collected either L. minor or E. crassipens, as these specimens cohabited only in two niches. V. cholera was isolated from both L. minor and E. crassipens roots. The isolated V. cholera showed the same biochemical characteristics as the pure V. cholera strain which was used as a control. The isolated V. cholera corresponded to V. cholera O1 El Tor Inaba, which is the same serotype related to the last outbreak in Mexico. For first time V. cholera El Tor Inaba has been isolated several years after the last emergence of cholera in Mexico. A viable and cultivable V. cholera strain, sourced from freshwater niches in E. crassipens and L. minor roots, suggests the importance of these plants as a permanent aquatic reservoir for these organisms. The monitoring of E. crassipens and L. minor is the responsibility of health institutions in order to evaluate the ongoing risks.


Setting positive end-expiratory pressure: lung and diaphragm ultrasound.
The purpose of this review is to summarize the role of lung ultrasound and diaphragm ultrasound in guiding ventilator settings with an emphasis on positive end-expiratory pressure (PEEP). Recent advances for using ultrasound to assess the effects of PEEP on the lungs and diaphragm are discussed. Lung ultrasound can accurately diagnose the cause of acute respiratory failure, including acute respiratory distress syndrome and can identify focal and nonfocal lung morphology in these patients. This is essential in determining optimal ventilator strategy and PEEP level. Assessment of the effect of PEEP on lung recruitment using lung ultrasound is promising, especially in the perioperative setting. Diaphragm ultrasound can monitor the effects of PEEP on the diaphragm, but this needs further validation. In patients with an acute exacerbation of chronic obstructive pulmonary disease, diaphragm ultrasound can be used to predict noninvasive ventilation failure. Lung and diaphragm ultrasound can be used to predict weaning outcome and accurately diagnose the cause of weaning failure. Lung and diaphragm ultrasound are useful for diagnosing the cause of respiratory failure and subsequently setting the ventilator including PEEP. Effects of PEEP on lung and diaphragm can be monitored using ultrasound.


The Profile of Moods States and Athletic Performance: A Meta-Analysis of Published Studies.
Researchers have extensively examined and reviewed the relationship of the profile of mood states (POMS) with sport performance since the 1970s. Two decades have passed since the last POMS quantitative review. Our overall objective was to quantify the POMS research with competitive athletes with a prospective measured POMS and a sport performance outcome in the published literature. Additionally, we tested potential moderators of the mental health model (i.e., sport duration, type, and skill) with meta-analytic techniques while considering potential risk bias across study sources. Based on a systematic review, the articles were found using EBSCO and comparing these articles with extensive past POMS in sport and exercise bibliographies. Search terms included profile of mood states (POMS) or iceberg profile or the mental health model with sport and performance or sports performance. For selection, articles must have reported data on competitive athletes, an athletic performance outcome, and a valid form of the POMS measured prospectively. After screening more than 600 articles for inclusion, 25 articles provided sufficient data for effect size calculations. The included articles spanned from 1975 to 2011, with 1497 unique participants. Hedges' g values were generally small for the six POMS scales: tension (-0.21), depression (-0.43), anger (-0.08), vigor (0.38), fatigue (-0.13), and confusion (-0.41). However, the total mood disturbance (TMD) score effect size was medium in magnitude at -0.53. When corrected for potential publication bias, the effect size values increased in magnitude for tension (-0.47), depression (-0.64), vigor (0.44), fatigue (-0.34), and TMD (-0.84). Moderator analyses for Terry's (1995) propositions and for risk of bias across studies, statistically, resulted in few differences based on conventional statistical significance (p < 0.05). Measured before performance, most of the POMS scales and TMD are reliable predictors of sport performance in competitive athletes across a wide variety of sports and athletic performance outcomes. Morgan's (1980, 1985) mental health model or iceberg profile minus anger is still a viable method for understanding and improving athletic performances.


[Paroxysmal nocturnal hemoglobinuria: from physiopathology to treatment].
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disorder, an acquired chronic hemolytic anemia, often associated with recurrent nocturnal exacerbations, recurrent infections, neutropenia, thrombocytopenia, and episodes of venous thrombosis. Its clinical course is highly variable. It frequently arises in association with bone marrow failure, particularly aplastic anemia and myelodysplastic syndrome. It is also an acquired thrombophilia, presenting with a variety of venous thrombosis, mainly manifested with intra-abdominal thrombosis, here the major cause of mortality. The triad of hemolytic anemia, pancytopenia, and thrombosis makes a truly unique clinical syndrome of PNH, which was reclassified from a purely acquired hemolytic anemia to a hematopoietic stem cell mutation defect of the phosphatidyl inositol glycanclass-A gene. This mutation results in an early block in the synthesis of glycosylphosphatidylinositol (GPI) anchors, responsible for binding membrane functional proteins. Among these proteins are the complement inhibitors, especially CD55 and CD59, that play a key role in protecting blood cells from complement cascade attack. Therefore, in PNH occurs an increased susceptibility of red cells to complement, and consequently, hemolysis. We here review PNH physiopathology, clinical course, and treatment options, especially eculizumab, a humanized monoclonal antibody that blocks the activation of terminal complement at C5 and prevents formation of the terminal complement complex, the first effective drug therapy for PNH.


Direct and maternal genetic covariances by age of dam for weaning weight.
Weaning weights of calves of dams at ages in years of 2, 3, and older were modeled to be three separate traits. Fixed effects were sex of calf-year of birth combinations for nine pure breeds and sex of calf-year of birth-generation for three composite populations. Random effects fitted for each trait were correlated direct and maternal genetic, maternal permanent environmental, and temporary environmental. Direct and maternal effects were correlated across traits. A multiple-trait, derivative-free REML algorithm was used to estimate the 30 (co)variance components. Number of animals per breed group ranged from 1,244 to 4,326. For the three traits for pure breeds, average proportions of phenotypic variance were .34, .31, and .27 for direct genetic; .16, .15, and .12 for maternal genetic; and .18, .20, and .17 for maternal environmental effects. Average correlations among the three traits were .84 for direct genetic, .78 for maternal genetic, and .71 for maternal environmental effects. Average of direct-maternal genetic correlations for pure breeds was .05. For the composite breeds, average proportions of phenotypic variances were .44, .46, and .36 for direct genetic; .06, .06, and .05 for maternal genetic; and .16, .14, and .14 for maternal environmental effects. Average correlations among the three traits were .93 for direct genetic, .76 for maternal genetic, and .85 for maternal environmental effects. Average direct-maternal genetic correlation was .09 for composites. No evidence was found for greater direct-maternal genetic correlation for earlier than for later ages of dam. Sign and magnitudes of direct-maternal genetic correlations seemed to differ among pure breeds and were reflected in composites from those parent breeds.


Education. Undergraduate research experiences: impacts and opportunities.
Most undergraduates give high ratings to research experiences. Studies report that these experiences improve participation and persistence, often by strengthening students' views of themselves as scientists. Yet, the evidence for these claims is weak. More than half the 60 studies reviewed rely on self-report surveys or interviews. Rather than introducing new images of science, research experiences may reinforce flawed images especially of research practices and conceptual understanding. The most convincing studies show benefits for mentoring and for communicating the nature of science, but the ideas that students learn are often isolated or fragmented rather than integrated and coherent. Rigorous research is needed to identify ways to design research experiences so that they promote integrated understanding. These studies need powerful and generalizable assessments that can document student progress, help distinguish effective and ineffective aspects of the experiences, and illustrate how students interpret the research experiences they encounter. To create research experiences that meet the needs of interested students and make effective use of scarce resources, we encourage systematic, iterative studies with multiple indicators of success.


Cholestasis-associated glucocorticoid overexposure does not increase atherogenesis.
Chronic glucocorticoid overexposure predisposes to the development of atherosclerotic cardiovascular disease in humans. Cholestatic liver disease is associated with increased plasma glucocorticoid levels. Here, we determined - in a preclinical setting - whether the chronic presence of cholestatic liver disease also induces a concomitant negative impact on atherosclerosis susceptibility. Hereto, regular chow diet-fed atherosclerosis-susceptible hypercholesterolemic apolipoprotein E (APOE)-knockout mice were treated with the bile duct toxicant alpha-naphthylisothiocyanate (ANIT) for 8 weeks. ANIT exposure induced the development of fibrotic cholestatic liver disease as evident from collagen deposits and compensatory bile duct hyperproliferation within the liver and the rise in plasma levels of bilirubin (+60%; P < 0.01) and bile acids (10-fold higher; P < 0.01). Adrenal weights (+22%; P < 0.01) and plasma corticosterone levels (+72%; P < 0.01) were increased in ANIT-treated mice. In contrast, atherosclerosis susceptibility was not increased in response to ANIT feeding, despite the concomitant increase in plasma free cholesterol (+30%; P < 0.01) and cholesteryl ester (+42%; P < 0.001) levels. The ANIT-induced hypercorticosteronemia coincided with marked immunosuppression as judged from the 50% reduction (P < 0.001) in circulating lymphocyte numbers. However, hepatic glucocorticoid signaling was not enhanced after ANIT treatment. It thus appears that the immunosuppressive effect of glucocorticoids is uncoupled from their metabolic effect under cholestatic disease conditions. In conclusion, we have shown that cholestatic liver disease-associated endogenous glucocorticoid overexposure does not increase atherosclerosis susceptibility in APOE-knockout mice. Our studies provide novel preclinical evidence for the observations that the hypercholesterolemia seen in cholestatic human subjects does not translate into a higher risk for atherosclerotic cardiovascular disease.


Caveolae compartmentalization of heme oxygenase-1 in endothelial cells.
The heme oxygenase (HO) and nitric oxide synthase (NOS) enzymes generate the gaseous signaling molecules carbon monoxide (CO) and nitric oxide, respectively. Constitutive NOSs localize to caveolae, and their activities are modulated by caveolin-1. Nothing is known of the localization of the inducible heme oxygenase-1 (HO-1) in plasma membrane caveolae. Thus, we examined the distribution and subcellular localization of HO-1, biliverdin reductase (BVR), and NADPH:cytochrome P450 reductase (NPR) in pulmonary artery endothelial cells. Each of these proteins localized in part to plasma membrane caveolae in endothelial cells. Inducers of HO-1 or overexpression of HO-1 increased the content of this protein in a detergent-resistant fraction containing caveolin-1. Inducible HO activity appeared in plasma membrane, cytosol, and isolated caveolae. In addition, caveolae contained endogenous BVR activity, supporting the same compartmentalization of both enzymes. Caveolin-1 physically interacted with HO-1, as shown by coimmunoprecipitation studies. HO activity dramatically increased in cells expressing caveolin-1 antisense transcripts, suggesting a negative regulatory role for caveolin-1. Conversely, caveolin-1 expression attenuated LPS-inducible HO activity. Since their initial characterization in 1969, HO enzymes have been described as endoplasmic reticulum-associated proteins. We demonstrate for the first time the localization of heme degradation enzymes to plasma membrane caveolae, and present novel evidence that caveolin-1 interacts with and modulates HO activity.


Prospects and Limitations of Transition Metal Dichalcogenide Laser Gain Materials.
Nanolasers operate with a minimal amount of active material and low losses. In this regime, single layers of transition-metal dichalcogenides (TMDs) are being investigated as next generation gain materials due to their high quantum efficiency. We provide results from microscopic gain calculations of highly excited TMD monolayers and specify requirements to achieve lasing with four commonly used TMD semiconductors. Our approach includes band-structure renormalizations due to excited carriers that trigger a direct-to-indirect band gap transition. As a consequence, we predict a rollover for the gain that limits the excitation regime where laser operation is possible. A parametrization of the peak gain is provided that is used in combination with a rate-equation theory to discuss consequences for experimentally accessible laser characteristics.


Plague in camels and its prevention in the USSR.
In 1954-56 a series of experiments was carried out in Central Asia, under the guidance of the author, in which camels were infected with plague by infesting them with Ixodes and Argas ticks which had previously fed on plague-infected laboratory animals. Subcutaneous, intradermal and intravenous injection was also used. The experiments showed that the camels varied markedly in their susceptibility to plague, which in any case was relatively low.Special investigations on plague prevention in camels are also reported. Vaccination with dried live vaccine injected in a single dose of 30 000 million organisms created a sufficiently high degree of immunity in adult animals. Spraying of the camels' coats with insecticide is also recommended.


[Sisomicin versus gentamicin. A comparison of antibacterial and pharmacokinetic properties (author's transl)].
In a comparison of the antibacterial in-vitro activity of sisomicin, gentamicin, and tobramycine, sisomicin showed a higher activity against E. coli, indole-positive Proteus spp. and organisms of the Klebsiella-Enterobacter-Serratia group, whereas tobramycine was superior against Pseudomonas spp. However, the differences in activity between sisomicin and gentamicin were only within one step of dilution which is hardly sufficient to guarantee a basic superiority of one or the other preparation for clinical purposes. In 12 healthy probands serum levels and renal elimination of sisomicin and gentamicin after a single intramuscular injection of 1 mg/kg body weight were investigated in a randomised change-over trial. With corresponding serum levels, almost identical elimination half-lives of 109 and 111 minutes, and recovery values of 84 and 88.4%, respectively, there were no significant differences in the pharmacokinetics of sisomicin and gentamicin. Thus in the antibacterial treatment of gentamicin-sensitive gram-negative organisms sisomicin presents an equally good alternative. With organisms only moderately sensitive or resistant to gentamicin, sisomicin, tobramycine and amikacin should be additionally tested.


The effect of montelukast on bronchial provocation tests and exhaled nitric oxide levels in asthmatic patients.
Leukotriene antagonist therapy in asthmatic patients alleviates symptoms and improves exercise tolerance, however the effect of these drugs on bronchial provocation tests and exhaled nitric oxide levels are less clearly established. To determine the effect of montelukast treatment on airway hyperresponsiveness to exercise, methacholine and adenosine-5'-monophosphate and on exhaled nitric oxide levels in steroid-naive asthmatics. Following a 2 week run-in period, 20 mild to moderate asthmatics were enrolled in an open label 6 week trial of oral montelukast-sodium therapy. Bronchial hyperreactivity (exercise, methacholine and adenosine-5'-monophosphate challenges) and exhaled nitric oxide levels were measured before and after the 6 week period. Montelukast treatment resulted in a significant improvement in exercise tolerance: median delta FEV1 20.0% (range 0-50) prior to treatment vs. 15.0% (range 0-50) post-treatment (P = 0.029). A significant difference was also observed for exhaled NO following therapy: median NO 16.0 ppb (range 7-41) vs. 13.0 (range 4.8-26) (P = 0.016). No change was seen in baseline lung function tests (FEV1, MEF50) or in the bronchial responsiveness (PC20) for methacholine and adenosine-5'-monophosphate. This study demonstrates that the leukotriene antagonist montelukast-sodium reduces bronchial hyperreactivity in response to exercise and reduces exhaled nitric oxide levels but has little effect on bronchial responsiveness to methacholine and adenosine challenges.


Metabolite gene regulation: imidazole and imidazole derivatives which circumvent cyclic adenosine 3',5'-monophosphate in induction of the Escherichia coli L-arabinose operon.
Imidazole, histidine, histamine, histidinol phosphate, urocanic acid, or imidazolepropionic acid were shown to induce the L-arabinose operon in the absence of cyclic adenosine 3',5'-monophosphate. Induction was quantitated by measuring the increased differential rate of synthesis of L-arabinose isomerase in Escherichia coli strains which carried a deletion of the adenyl cyclase gene. The crp gene product (cyclic adenosine 3',5'-monophosphate receptor protein) and the araC gene product (P2) were essential for induction of the L-arabinose operon by imidazole and its derivatives. These compounds were unable to circumvent the cyclic adenosine 3',5'-monophosphate in the induction of the lactose or the maltose operons. The L-arabinose regulon was catabolite repressed upon the addition of glucose to a strain carrying an adenyl cyclase deletion growing in the presence of L-arabinose with imidazole. These results demonstrated that several imidazole derivatives may be involved in metabolite gene regulation (23).


Genetic parameters of endocrine fertility traits based on in-line milk progesterone profiles in Swedish Red and Holstein dairy cows.
Evaluating fertility traits based on endocrine progesterone profiles is becoming a promising option to improve dairy cow fertility. Several studies have been conducted on endocrine fertility traits, mainly in the Holstein breed. In this study, focusing also on the Swedish Red (SR) breed, genetic parameters were estimated for classical and endocrine fertility traits, the latter based on in-line milk progesterone records obtained for 14 Swedish herds using DeLaval Herd Navigator (DeLaval International, Tumba, Sweden). A total of 210,403 observations from 3,437 lactations of 1,107 SR and 1,538 Holstein cows were used. Mixed linear animal models were used for estimation of genetic parameters. Least squares means analysis showed that Holstein cows had a 2.5-d-shorter interval from calving to commencement of luteal activity (C-LA) and longer length of first inter-ovulatory interval (IOI) than SR cows. The highest mean interval for C-LA, IOI, and first luteal phase length (LPL) was observed in the fourth parity. The incidence of short (<18 d), normal, (18-24 d), and long (>24 d) IOI was 29.3, 40.7, and 30%, respectively. Genetic analysis indicated moderate heritability (h2) for C-LA (h2 = 0.24), luteal activity during the first 60 d in milk (LA60, h2 = 0.15), proportion of samples with luteal activity (PLA, h2 = 0.13), and calving to first heat (CFH, h2 = 0.18), and low heritability estimates for LPL (h2 = 0.08) and IOI (h2 = 0.03) in the combined data set for both breeds. Similar heritability estimates were obtained for each breed separately except for IOI and LPL in SR cows, for which heritability was estimated to be zero. Swedish Red cows had 0.01 to 0.06 higher heritability estimates for C-LA, LA60, and PLA than did Holstein cows. Calving interval had moderate heritability among the classical traits for Holstein and the combined data set, but h2 was zero for SR. Commencement of luteal activity had a strong genetic correlation with LA60 (mean ± SE; -0.88 ± 0.06), PLA (-0.72 ± 0.11), and CFH (0.90 ± 0.04). Similarly, CFH had a strong genetic correlation with IOI (0.98 ± 0.20). Number of inseminations per series showed a weak genetic correlation with all endocrine traits except IOI. Overall, endocrine traits had higher heritability estimates than classical traits in both breeds, and may have a better potential to explain the actual reproductive status of dairy cows than classical traits. This might favor inclusion of some endocrine fertility traits-especially those related to commencement of luteal activity-as selection criteria and breeding goal traits if recording becomes more common in herds. Further studies on genetic and genomic evaluations for endocrine fertility traits may help to provide firm conclusions. A prerequisite is that the data from automatic devices be made available to recording and breeding organizations in the future and included in a central database.


Determination of dimethylarginine levels in rats using HILIC-MS/MS: an in vivo microdialysis study.
Nitric oxide (NO) is one of the most important mediators and neurotransmitters and its levels change under pathological conditions. NO production may be regulated by endogenous nitric oxide synthase (NOS) inhibitors, in particular asymmetric dimethylarginine (ADMA). Most of the interest is focused on ADMA, since this compound is present in plasma and urine and accumulation of ADMA has been described in many disease states but little is known about cerebrospinal fluid (CSF) concentrations of this compound and of its structural isomer symmetric dimethylarginine (SDMA). To determine the levels of methylarginines, we here present a new hydrophilic interaction chromatography (HILIC)-MS/MS method for the precise determination of these substances in CSF from microdialysis samples of rat prefrontal cortex (PFC). The method requires only minimal sample preparation and features isotope-labelled internal standards.


Characterization of the Trans-Epithelial Transport of Green Tea (C. sinensis) Catechin Extracts with In Vitro Inhibitory Effect against the SARS-CoV-2 Papain-like Protease Activity.
This work describes an untargeted analytical approach for the screening, identification, and characterization of the trans-epithelial transport of green tea (Camellia sinensis) catechin extracts with in vitro inhibitory effect against the SARS-CoV-2 papain-like protease (PLpro) activity. After specific catechin extraction, a chromatographic separation obtained six fractions were carried out. The fractions were assessed in vitro against the PLpro target. Fraction 5 showed the highest inhibitory activity against the SARS-CoV-2 PLpro (IC50 of 0.125 μg mL-1). The untargeted characterization revealed that (-)-epicatechin-3-gallate (ECG) was the most abundant compound in the fraction and the primary molecule absorbed by differentiated Caco-2 cells. Results indicated that fraction 5 was approximately 10 times more active than ECG (IC50 value equal to 11.62 ± 0.47 μg mL-1) to inhibit the PLpro target. Overall, our findings highlight the synergistic effects of the various components of the crude extract compared to isolated ECG.


Outcome of posttraumatic fibromyalgia: a 3-year follow-up of 78 cases of cervical spine injuries.
To assess the outcome of fibromyalgia syndrome (FMS) after cervical spine injury. Seventy-eight of 102 (77%) patients with neck injury were recruited 3 years after the original study in 1996. Twenty of the original 22 patients with FMS were available for reevaluation in 1999. A count of 18 tender points was conducted by thumb palpation, and tenderness thresholds were assessed by dolorimetry at 9 tender sites. All patients were interviewed about the presence and severity of neck and FMS-related symptoms. FMS was diagnosed by using the American College of Rheumatology 1990 criteria. Additional questions assessed measures of physical functioning and quality of life. Sixty percent of the 20 patients who had FMS in 1996 still had it 3 years later. All the 11 women with FMS, but only 1 of the 9 men with FMS, met FMS criteria in 1999. Only 1 of 58 patients who had no FMS in 1996 developed FMS. The quality of life scores for most patients improved, their tenderness scores decreased, and all remained employed. The outcome of posttraumatic FMS in patients with neck injury seems to be more favorable in men than in women; however, this finding should be interpreted with caution because of the small sample. Patients who do not develop FMS within 1 year of neck injury have a low probability of developing FMS in the future, comparable to the incidence of FMS in the general population.


Idiopathic portal hypertension and its pathology.
Idiopathic portal hypertension (IPH) is a disorder of unknown etiology, clinically characterized by portal hypertension (varices and portosystemic collateral vessels), splenomegaly, and anemia (hypersplenism). A similar disorder is called noncirrhotic portal fibrosis in India, and hepatoportal sclerosis seems to be the counterpart in the United States. This disease is uncommon in developed countries. Middle-aged women are more prone to IPH in Japan. The liver has no cirrhosis or pseudonodule formation, and the principal pathologic changes are considerable portal fibrosis, devastation of intrahepatic terminal portal radicles, and parenchymal atrophy of the liver secondary to portal malperfusion. The characteristic portal hemodynamics include intrahepatic presinusoidal portal hypertension, increased splenic and portal vein blood flow, and increased intrahepatic portal resistance. The prognosis is generally good depending on the management of bleeding varices. Although the etiology is obscure, certain immunologic abnormalities seem to play an etiologic role in Japanese patients, and the incidence has markedly declined in recent years in Japan, indirectly suggesting a role of infection. The theory that IPH represents an undiagnosed intrahepatic portal vein thrombosis is refuted.


Atorvastatin prevents ATP-driven invasiveness via P2X7 and EHBP1 signaling in PTEN-expressing prostate cancer cells.
Epidemiological studies indicate that statins, cholesterol-lowering drugs, prevent aggressive prostate cancer and other types of cancer. Employing essentially non-prostate cell lines, we previously showed that statins rapidly downregulate nuclear levels of phosphorylated Akt via P2X7, a purinergic receptor recently implicated in invasive growth. Here, we present studies on phosphatase and tensin homolog deleted on chromosome 10 (PTEN)-positive prostatic cells. We document an involvement of EH domain-binding protein 1 (EHBP1), previously associated with aggressive prostate cancer and insulin-stimulated trafficking and cell migration, in P2X7 signaling. We also show that EHBP1 is essential for an anti-invasive effect of atorvastatin. Furthermore, EHBP1 interacted with P-Rex1, a guanine nucleotide exchange factor previously implicated in invasive growth. Mevalonate did not prevent this anti-invasive effect of atorvastatin. These data indicate that atorvastatin modulates invasiveness via P2X7, EHBP1 and P-Rex1. Interestingly, the interaction between EHBP1 and P-Rex1 was not induced by extracellular adenosine triphosphate (ATP), the endogenous P2X7 ligand, and statins counteracted invasiveness stimulated by extracellular ATP. In support of these experimental data, a population-based genetic analysis showed that a loss of function allele in the P2X7 gene (rs3751143) associated with non-aggressive cancer, and the common allele with aggressive cancer. Our data indicate a novel signaling pathway that inhibits invasiveness and that is druggable. Statins may reduce the risk of aggressive prostate cancer via P2X7 and by counteracting invasive effects of extracellular ATP.


The use of alkaline hydrolysis as a novel strategy for chloroform remediation: the feasibility of using construction wastes and evaluation of carbon isotopic fractionation.
Laboratory and field-scale pilot experiments were performed to evaluate the feasibility of chloroform degradation by alkaline hydrolysis and the potential of δ(13)C values to assess this induced reaction process at contaminated sites. In batch experiments, alkaline conditions were induced by adding crushed concrete (pH 12.33 ± 0.07), a filtered concrete solution (pH 12.27 ± 0.04), a filtered cement solution (pH 12.66 ± 0.02) and a pH 12 buffer solution (pH 11.92 ± 0.11). The resulting chloroform degradation after 28 days was 94, 96, 99, and 72%, respectively. The experimental data were described using a pseudo-first-order kinetic model, resulting in pseudo-first-order rate constant values of 0.10, 0.12, 0.20, and 0.05 d(-1), respectively. Furthermore, the significant chloroform carbon isotopic fractionation associated with alkaline hydrolysis of chloroform (-53 ± 3‰) and its independence from pH in the admittedly limited tested pH range imply a great potential for the use of δ(13)C values for in situ monitoring of the efficacy of remediation approaches based on alkaline hydrolysis. The carbon isotopic fractionation obtained at the lab scale allowed the calculation of the percentage of chloroform degradation in field-scale pilot experiments where alkaline conditions were induced in two recharge water interception trenches filled with concrete-based construction wastes. A maximum of approximately 30-40% of chloroform degradation was achieved during the two studied recharge periods. Although further research is required, the treatment of chloroform in groundwater through the use of concrete-based construction wastes is proposed. This strategy would also imply the recycling of construction and demolition wastes for use in value-added applications to increase economic and environmental benefits.


Towards Model-Free Tool Dynamic Identification and Calibration Using Multi-Layer Neural Network.
In robot control with physical interaction, like robot-assisted surgery and bilateral teleoperation, the availability of reliable interaction force information has proved to be capable of increasing the control precision and of dealing with the surrounding complex environments. Usually, force sensors are mounted between the end effector of the robot manipulator and the tool for measuring the interaction forces on the tooltip. In this case, the force acquired from the force sensor includes not only the interaction force but also the gravity force of the tool. Hence the tool dynamic identification is required for accurate dynamic simulation and model-based control. Although model-based techniques have already been widely used in traditional robotic arms control, their accuracy is limited due to the lack of specific dynamic models. This work proposes a model-free technique for dynamic identification using multi-layer neural networks (MNN). It utilizes two types of MNN architectures based on both feed-forward networks (FF-MNN) and cascade-forward networks (CF-MNN) to model the tool dynamics. Compared with the model-based technique, i.e., curve fitting (CF), the accuracy of the tool identification is improved. After the identification and calibration, a further demonstration of bilateral teleoperation is presented using a serial robot (LWR4+, KUKA, Germany) and a haptic manipulator (SIGMA 7, Force Dimension, Switzerland). Results demonstrate the promising performance of the model-free tool identification technique using MNN, improving the results provided by model-based methods.


Beyond the rhetoric: strategies for implementing culturally effective practice with children, families, and communities.
Culturally effective practice remains elusive within child welfare agencies. Recognizing the hierarchical nature of becoming culturally competent, this article presents specific strategies that enhance cultural effectiveness at the individual, interprofessional, middle management, and upper management levels. The approaches evolve from a five-stage model of change: precontemplation, contemplation, preparation, action, and maintenance. Becoming culturally competent requires a clear assessment of where the individual practitioner and agency are on the change continuum. The article also explores barriers to culturally competent practice, with a focus on multilevel strategies that work within child welfare agencies.


Turning to religion as a mediator of the relationship between hopelessness and job satisfaction during the COVID-19 pandemic among individuals representing the uniformed services or working in professions of public trust in Poland.
During the COVID-19 pandemic individuals performing uniformed service or working in a profession of public trust were particularly exposed to chronic stress. The exposure to stress contributes to a decrease in quality of life across various domains, including professional performance. The perceived mental difficulties can lead to a feeling of hopelessness which, in turn can generate a decrease in job satisfaction. Religiosity is a factor which, in stress-inducing conditions, not only stops the spiral of perceived resource losses but also triggers gains in the resources possessed. The aim of the study was to assess the preference for positive religious coping strategies, namely turning to religion as a mediator for the relationship between perceived hopelessness and job satisfaction in the individuals declaring religiosity during the COVID-19 pandemic. The analysis has been performed based on the Conservation of Resources theory (COR). The study encompassed 238 individuals representing the uniformed services or working in professions of public trust in Poland. The Inventory for Measuring Coping with Stress (MINI-COPE) and the Beck Hopelessness Scale (BHS) were used in the research. The mediating role of turning to religion in relationship between perceived hopelessness and job satisfaction was confirmed only in the group of women. The relationship found in this group indicates that perceived hopelessness is alleviated by turning to religion, which simultaneously leads to an increase in job satisfaction. The obtained results prove that counselling should be standard practice after potentially traumatic events in the workplace; moreover, emotional and/or instrumental support should be offered along with spiritual one.


Global ethics and principlism.
This article examines the special relation between common morality and particular moralities in the four-principles approach and its use for global ethics. It is argued that the special dialectical relation between common morality and particular moralities is the key to bridging the gap between ethical universalism and relativism. The four-principles approach is a good model for a global bioethics by virtue of its ability to mediate successfully between universal demands and cultural diversity. The principle of autonomy (i.e., the idea of individual informed consent), however, does need to be revised so as to make it compatible with alternatives such as family- or community-informed consent. The upshot is that the contribution of the four-principles approach to global ethics lies in the so-called dialectical process and its power to deal with cross-cultural issues against the background of universal demands by joining them together.


Pupils returning to primary schools in England during 2020: rapid estimations of punctual COVID-19 infection rates.
Drawing on risk methods from volcano crises, we developed a rapid COVID-19 infection model for the partial return of pupils to primary schools in England in June and July 2020, and a full return in September 2020. The model handles uncertainties in key parameters, using a stochastic re-sampling technique, allowing us to evaluate infection levels as a function of COVID-19 prevalence and projected pupil and staff headcounts. Assuming average national adult prevalence, for the first scenario (as at 1 June 2020) we found that between 178 and 924 [90% CI] schools would have at least one infected individual, out of 16 769 primary schools in total. For the second return (July), our estimate ranged between 336 (2%) and 1873 (11%) infected schools. For a full return in September 2020, our projected range was 661 (4%) to 3310 (20%) infected schools, assuming the same prevalence as for 5 June. If national prevalence fell to one-quarter of that, the projected September range would decrease to between 381 (2%) and 900 (5%) schools but would increase to between 2131 (13%) and 9743 (58%) schools if prevalence increased to 4× June level. When regional variations in prevalence and school size distribution were included in the model, a slight decrease in the projected number of infected schools was indicated, but uncertainty on estimates increased markedly. The latter model variant indicated that 82% of infected schools would be in areas where prevalence exceeded the national average and the probability of multiple infected persons in a school would be higher in such areas. Post hoc, our model projections for 1 September 2020 were seen to have been realistic and reasonable (in terms of related uncertainties) when data on schools' infections were released by official agencies following the start of the 2020/2021 academic year.


Grafting of aminated oligogalacturonans onto Douglas fir barks. A new route for the enhancement of their lead (II) binding capacities.
Chemical modification of Douglas fir bark and its subsequent utilization in adsorption of PbII from aqueous solutions was investigated. A new approach to enhance the natural properties of bark by covalent grafting of oligogalacturonans was developed. The polysaccharidic moiety of barks was functionalized by periodate oxidation and derivatized after reductive amination in presence of aminated oligogalacturonic acid. PbII adsorption isotherms of derivatized barks were then determined and compared with the capabilities of crude barks using the Langmuir adsorption model in terms of affinity (b) and maximum binding capacities (q(max)). Derivatization resulted in significant enhancements of the q(max) values (up to x8), along with little change of the affinity parameter.


Toxic gas clouds: effects and implications of dry deposition on concentration.
The influence of the dry deposition process on concentration pertaining to toxic gas clouds was investigated by model calculations. Three main release scenarios were simulated, with nine micrometeorological cases considered for each. To compare and confirm the results, two model types, a stochastic particle model and a box-type model, were independently used to simulate many of the different cases. The results showed that the effects of dry deposition may be strong for releases at, or confined close to the ground, e.g. neutral or unstable stratification can cause higher concentrations than stable stratification after 10-15 km. Risk distances are in turn affected and may be substantially shortened, e.g. for a zero-height release like that from an evaporating pool, a 50% reduction in total airborne substance may occur within 500 m at a low wind velocity and neutral or stable stratification.


Comparison of ejection fraction and zonal mean velocity of myocardial fiber shortening.
To determine the extent of cardiac involvement until a diminished ejection fraction (EF) is present, zonal mean velocity of circumferential fiber shortening (Vcf) was measured from the left ventriculogram in 36 patients. The longitudinal axis (apex to mid-point of the aortic valve plane) in right anterior oblique view was divided into four equal parts by three perpeendicular chords. Zonal Vct and percent shortening along the proximal, middle and distal chords were measured. The results of this study indicate that a normal EF is frequently associated with a reduced Vct in one or even two zones. A reduced EF is generally accompanied by a diminished Vct in all three zones of the heart. In addition, a close correlation was found between zonal Vct and percent shortening. Hence the latter, which is much simpler to measure, can be instead of Vct Ejection fraction as a measure of myocardial performance is not as sensitive as Vct, especially in hearts with asynchrony of contraction.


Methyl-accepting chemotaxis protein III and transducer gene trg.
A comparison of the two-dimensional gel patterns of methyl-3H- and 35S-labeled membrane proteins from trg+ and trg null mutant strains of Escherichia coli indicated that the product of trg is probably methyl-accepting chemotaxis protein III. Like the other known methyl-accepting chemotaxis proteins, the trg product is a membrane protein that migrates as more than one species in sodium dodecyl sulfate-polyacrylamide gel electrophoresis, implying that it too is multiple methylated. It appears likely that all chemoreceptors are linked to the tumble regulator through a single class of membrane protein transducers which are methyl-accepting proteins. Three transducers are coded for by genes tsr, tar, and, probably, trg. Another methyl-accepting protein, which is not related to any of these genes, was observed.


The effect of partial deglycosylation on the structure of alpha1-acid glycoprotein.
Changes in structure of alpha1-acid glycoprotein were followed after deglycosylation with neuraminidase, peptide N-glycohydrolase F or with a mixture of exoglycosidases. Partially deglycosylated preparations of alpha1-acid glycoprotein free of sialic acids, one complete saccharide component, sialic acids and one saccharide component and sialic acids and some of the external saccharides were obtained. The effect of these changes in saccharide components on the glycoprotein structure was studied by temperature perturbation difference spectroscopy, fluorescence spectroscopy, fourth-derivative of absorption spectra and spectra of CD. Partial deglycosylation resulted in transformation of the molecule to a more compact state in which phenylalanyl residues were even more buried, tyrosyl residues became more uniform and tryptophyl residues were less exposed. The content of ordered secondary structures decreased. The thermal stability of the molecule was not significantly affected. Removal of one of the five saccharide components from the native molecule had apparently deeper effect than total desialyzation of the glycoprotein.


A lifetime of aldosterone excess: long-term consequences of altered regulation of aldosterone production for cardiovascular function.
Up to 15% of patients with essential hypertension have inappropriate regulation of aldosterone; although only a minority have distinct adrenal tumors, recent evidence shows that mineralocorticoid receptor activation contributes to the age-related blood pressure rise and illustrates the importance of aldosterone in determining cardiovascular risk. Aldosterone also has a major role in progression and outcome of ischemic heart disease. These data highlight the need to understand better the regulation of aldosterone synthesis and its action. Aldosterone effects are mediated mainly through classical nuclear receptors that alter gene transcription. In classic epithelial target tissues, signaling mechanisms are relatively well defined. However, aldosterone has major effects in nonepithelial tissues that include increased synthesis of proinflammatory molecules and reactive oxygen species; it remains unclear how these effects are controlled and how receptor specificity is maintained. Variation in aldosterone production reflects interaction of genetic and environmental factors. Although the environmental factors are well understood, the genetic control of aldosterone synthesis is still the subject of debate. Aldosterone synthase (encoded by the CYP11B2 gene) controls conversion of deoxycorticosterone to aldosterone. Polymorphic variation in CYP11B2 is associated with increased risk of hypertension, but the molecular mechanism that accounts for this is not known. Altered 11beta-hydroxylase efficiency (conversion of deoxycortisol to cortisol) as a consequence of variation in the neighboring gene (CYP11B1) may be important in contributing to altered control of aldosterone synthesis, so that the risk of hypertension may reflect a digenic effect, a concept that is discussed further. There is evidence that a long-term increase in aldosterone production from early life is determined by an interaction of genetic and environmental factors, leading to the eventual phenotypes of aldosterone-associated hypertension and cardiovascular damage in middle age and beyond. The importance of aldosterone has generated interest in its therapeutic modulation. Disadvantages associated with spironolactone (altered libido, gynecomastia) have led to a search for alternative mineralocorticoid receptor antagonists. Of these, eplerenone has been shown to reduce cardiovascular risk after myocardial infarction. The benefits and disadvantages of this therapeutic approach are discussed.


SNP discovery in proso millet (Panicum miliaceum L.) using low-pass genome sequencing.
Domesticated ~10,000 years ago in northern China, Proso millet (Panicum miliaceum L.) is a climate-resilient and human health-promoting cereal crop. The genome size of this self-pollinated allotetraploid is 923 Mb. Proso millet seeds are an important part of the human diet in many countries. In the USA, its use is restricted to the birdseed and pet food market. Proso millet is witnessing gradual demand in the global human health and wellness food market owing to its health-promoting properties such as low glycemic index and gluten-free. The breeding efforts for developing improved proso millet cultivars are hindered by the dearth of genomic resources available to researchers. The publication of the reference genome and availability of cost-effective NGS methodologies could lead to the identification of high-quality genetic variants, which can be incorporated into breeding pipelines. Here, we report the identification of single-nucleotide polymorphisms (SNPs) by low-pass (1×) genome sequencing of 85 diverse proso millet accessions from 23 different countries. The 2 × 150 bp Illumina paired-end reads generated after sequencing were aligned to the proso millet reference genome. The resulting sequence alignment information was used to call SNPs. We obtained 972,863 bi-allelic SNPs after quality filtering of the raw SNPs. These SNPs were used to assess the population structure and phylogenetic relationships among the accessions. Most of the accessions were found to be highly inbred with heterozygosity ranging between .05 and .20. Principal component analysis (PCA) showed that PC1 (principal component) and PC2 explained 19% of the variability in the population. PCA also clustered all the genotypes into three groups. A neighbor-joining tree clustered the genotypes into four distinct groups exhibiting diverse representation within the population. The SNPs identified in our study could be used for molecular breeding and genetics research (e.g., genetic and association mapping, and population genetics) in proso millet after proper validation.


Amino acid-sequence variability at the N-terminal extra piece of mouse immunoglobulin light-chain precursors of the same and different subgroups.
The proteins programmed in the wheat-germ cell-free system by the mRNA coding for the MOPC-63 mouse myeloma L (light) chain were labelled with six radioactive amino acids: [35S]methionine, [4,5-3H]leucine, [3,4-3H]proline, [3-3H]serine, [4,5-3H]isoleucine or [2,3-3H]alanine. Amino acid-sequence analyses showed that over 90% of the total cell-free product was one homogeneous protein, which corresponds to the MOPC-63 L-chain precursor. In this precursor an extra piece, 20 amino acid residues in length, precedes the N-terminus of the mature L chain. The extra piece contains one methionine residue at the N-terminus, six leucine residues, which are clustered in two triplets at positions 6, 7, 8 and 11, 12, 13, one proline residue at position 16, and one serine residue at position 18. The closely gathered leucine residues, as well as their abundance (30%), suggest that the extra-piece moiety is hydrophobic. In the precursors, the extra piece is coupled to the variable region of the L chain. Partial sequences of precursors of L chains of the same and different subgroups that were labelled with the above six radioactive amino acids indicate that the extra piece is part of the variable region. Thus the precursors of MOPC-63 and MOPC-321 L chains, which are of the same subgroup, have extra pieces of identical size (20 residues), and so far their partial sequences are also identical (see above). On the other hand, in the precursor of MOPC-41 L chain, which is of a different subgroup, the extra piece is 22 residues in length. Further, the sequence of the MOPC-41 extra piece differs in at least ten positions from sequences of the extra pieces of the precursors of MOPC-63 and MOPC-321 L chains.


Prior cholecystokinin exposure sensitizes islets of Langerhans to glucose stimulation.
Prior, short-term exposure of isolated perifused islets to cholecystokinin (CCK8S) sensitizes them to subsequent glucose stimulation. This sensitization effect develops quickly and persists long after the removal of CCK8S from the perifusion medium. Continued binding of CCK8S to its receptor on the beta-cell and the increase in glucose metabolism noted with glucose stimulation are essential for the full expression of this response. This sensitization process may play an integral role in the postulated incretin effect of the peptide.


Pudendal nerve neuralgia after hip arthroscopy: retrospective study and literature review.
Pudendal nerve neurapraxia is a classic complication after traction on the fracture table. Diagnosis, however, is difficult and often overlooked, especially after arthroscopy in traction on fracture table; incidence is therefore not known exactly. The study hypothesis was that incidence of pudendal nerve neuropathy exceeds 1% after hip arthroscopy. Results for 150 patients (79 female, 71 male) undergoing hip arthroscopy between 2000 and 2010 were analyzed retrospectively. The principal assessment criterion was onset of pudendal neuralgia. Secondary criteria were risk factors (history, surgery time, type of anesthesia), associated complications, onset to diagnosis interval and pattern of evolution. At a mean 93 months' follow-up, there were 3 cases (2 women, 1 man) (2%) of pure sensory pudendal neuralgia; 2 concerned labral lesion resection and 1 osteochondromatosis. Surgery time ranged from 60 to 120min, under general anesthesia with curarization. Time to diagnosis was 3 weeks. No complementary examinations were performed. Spontaneous resolution occurred at 3 weeks to 6 months. No significant risk factors emerged. The present study found 2% incidence of pudendal neuralgia, with no risk factors emerging from analysis. Prevention involves limiting traction force and duration by using a large pelvic support (diameter>8-10cm). Patient information and postoperative screening should be systematic. Level IV. Retrospective study.


Longitudinal assessment of coronary plaque volume change related to glycemic status using serial coronary computed tomography angiography: A PARADIGM (Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography Imaging) substudy.
Data on the impact of glycemic status on coronary plaque progression have been limited. This study evaluated the association between glycemic status and coronary plaque volume change (PVC) using coronary computed tomography angiography (CCTA). A total of 1296 subjects (61 ± 9, 56.9% male) who underwent serial CCTA with available glycemic status were enrolled and analyzed from the Progression of AtheRosclerotic PlAque DetermIned by Computed TomoGraphic Angiography IMaging (PARADIGM) registry. The median inter-scan period was 3.2 (2.6-4.4) years. Quantitative assessment of coronary plaques was performed at both scans. All participants were categorized into the following groups according to glycemic status: normal, pre-diabetes (pre-DM), and diabetes mellitus (DM). During the follow-up, significant differences in PVC (normal: 51.3 ± 83.3 mm3 vs. pre-DM: 51.0 ± 84.3 mm3 vs. DM: 72.6 ± 95.0 mm3; p < 0.001) and annualized PVC (normal: 14.9 ± 24.9 mm3 vs. pre-DM: 15.7 ± 23.8 mm3 vs. DM: 21.0 ± 27.7 mm3; p = 0.001) were observed among the 3 groups. Compared with normal individuals, individuals with pre-DM showed no significant differences in the adjusted odds ratio (OR) for plaque progression (PP) (1.338, 95% confidence interval [CI] 0.967-1.853; p = 0.079). However, the adjusted OR for PP was higher in DM individuals than in normal individuals (1.635, 95% CI 1.126-2.375; p = 0.010). DM had an incremental impact on coronary PP, but pre-DM appeared to have no significant association with an increased risk of coronary PP after adjusting for confounding factors. ClinicalTrials.govNCT02803411.


Nurse practitioners leading the way: An exploratory study on the added value of nurse practitioners in outpatient care in the Netherlands.
Many Dutch nurse practitioners (NPs) work together with physicians and specialized nurses (SNs) in outpatient clinics, although the latter have questioned the added value of NPs in the outpatient clinic. Clarification of the distinction between and the added value of both nursing professions in relation to each other could lead to optimal use of the unique competencies of each type of nurse. To explore NPs' perspectives on their added value in relation to SNs in the outpatient clinic. Data were analyzed by Braun and Clarke's thematic analysis. The CanMEDS competences were used to identify the NPs' comments about their practice. Twelve semi-structured interviews were conducted with NPs from two hospital settings. The added value of NPs was most evident in: nursing leadership, integrating care and cure and performing an expert level of nursing expertise, and competencies in science. To optimize their roles, NPs and SNs need to make all team members aware of their unique competences and promote role clarification. This study provides barriers in barriers that influence optimal positioning of NPs within the interdisciplinary team, stresses the importance of discussion on the optimal skill mix within the interdisciplinary team, and describes the NPs' leadership role because this is the encompassing link between the main competencies of their practice. Addressing and overcoming these findings could improve the NPs' positioning and effective collaboration within (the outpatient clinic's) interprofessional teams.


Oxytocin treatment in children with Prader-Willi syndrome: A double-blind, placebo-controlled, crossover study.
Prader-Willi syndrome (PWS) is a rare, complex multisystem genetic disorder which includes hypothalamic dysfunction, hyperphagia, cognitive and behavioral problems, increased anxiety, and compulsive behaviors. Individuals with PWS have a deficit of oxytocin producing neurons in the paraventricular nucleus of the hypothalamus. Oxytocin plays a role in regulation of feeding behaviors, social interactions, and emotional reactivity, which are all issues that significantly affect the quality of life for individuals with this syndrome. We performed a double-blind, placebo-controlled, crossover study in 24 children with PWS at three academic institutions using 5 days of intranasal oxytocin (IN-OT) or 5 days of intranasal placebo spray, followed by a 4 week washout period, and then patients returned for 5 days of treatment with the alternate source. Questionnaires, including the Aberrant Behavior Checklist, Social Responsiveness Scale, Repetitive Behavior Scale - Revised, and the Hyperphagia Questionnaire, as well as Clinical Global Impression scales were administered. Blood testing for sodium, potassium, and glucose levels on days 2, 4, and 6, and a 24 hr diet recall. All scales factor improvement from Day 3 to Day 6 favored oxytocin over placebo. No single factor showed a statistically significant difference (P < 0.05) between groups at Day 6. The drug effect appeared to be diminished at Day 14. There was no evidence of a difference between oxytocin and placebo in safety lab parameters, 60 min post dose vital signs, weight, or diet parameters. The results from this study suggest that low dose intranasal oxytocin is safe for individuals with PWS and may result in reduction in appetite drive, and improvements in socialization, anxiety, and repetitive behaviors. Further, long-term studies with a larger population of participants are necessary to confirm these findings. The results of this study are encouraging that oxytocin may be a safe and effective treatment for many of the issues that negatively impact individuals with PWS.


Genetic testing for spinocerebellar ataxias in patients diagnosed as Parkinson's disease in Bangladesh.
This study was conducted to find out Spinocerebellar Ataxias (SCA) by genetic analysis from those patients presenting with Parkinsonism in the Neurology department of Mymensingh Medical College Hospital, Bangladesh. A sample of about 5ml blood was collected by venipuncture in EDTA tube after having informed consent from each patients and healthy individual, with due Institutional Ethical committee approval for genetic study of 7 healthy people and 9 patients. The neurological disorder along with a complete physical and/or psychological, as well as family history and demographic data was recorded with a prescribed questionnaire by the neurologists of Mymensingh Medical College Hospital. Extraction of genomic DNA from the venous blood using Flexi Gene DNA kit (Qiagen, Japan) was performed in Faculty of Veterinary Science, Bangladesh Agricultural University, Mymensingh, Bangladesh. The extracted DNA was stored, accumulated and then were sent to Division of Clinical Genetics, Department of Medical Genetics, Osaka University Medical School, Suita, Osaka 565 0871, Japan for PCR and further analysis. PCR amplification of the CAG repeat was performed for the SCA1, SCA2, SCA3, SCA6 loci using primers SCA1N-F1 and SCA1N-R1, SCA2-F1 and SCA2-R1, MJDF1 and MJDR1, SCA6-F1 and SCA6-R1, respectively. SCA1 PCR of both healthy individual and suspected Parkinsons Disease (PD) patients DNA was found 250 bp (no. of CAG repeats=36). SCA2 PCR products reveal the DNA products of about 150 bp (no. of CAG repeats=23) except one patient that was suspected and it was sequenced and revealed 175bp (no. of CAG repeats=30). SCA3 PCR product size of both healthy individual and patient DNA was within 250 (no. of CAG repeats=11) to 300 bp (no. of CAG repeats=28) except one patient which was about 320 bp and its CAG repeats was about 34. SCA6 PCR product size of both healthy individual and patient DNA was about 150 bp (no. of CAG repeats=16).


Effect of repeated exposure to AQUI-S® on the viability and growth of Neoparamoeba perurans.
There have been recent efforts amongst immunologists to develop approaches for following individual fish during challenges with viral and bacterial pathogens. This study contributes to assessing the feasibility of using such approaches to study amoebic gill disease (AGD). Neoparamoeba perurans, agent of AGD, has been responsible for widespread economic and fish loss in salmonid aquaculture. With the emergence of AGD in Europe, research into infection dynamics and host response has increased. This study investigated the effect of repeat exposure to anaesthesia, a necessary requirement when following disease progression in individual fish, on N. perurans. In vitro cultures of N. perurans were exposed every 4 days over a 28-day period to AQUI-S® (isoeugenol), a popular anaesthetic choice for AGD challenges, at a concentration and duration required to sedate post-smolt salmonids. Population growth was measured by sequential counts of amoeba over the period, while viability of non-attached amoeba in the culture was assessed with a vital stain. AQUI-S® was found to be a suitable choice for in vivo ectoparasitic challenges with N. perurans during which repetitive anaesthesia is required for analysis of disease progression.


Downregulation of TSPAN13 by miR-369-3p inhibits cell proliferation in papillary thyroid cancer (PTC).
Previous studies demonstrated dysregulation of different microRNAs in thyroid cancer. Tetraspanins (TSPANs) are cell surface proteins with critical roles in many cellular processes, and implications in tumor development. Here we investigated the role of miR-369-3p in papillary thyroid cancer (PTC) and its association with TSPAN13. miR-369-3p and the TSPAN13 gene expression profiles of 513 thyroid cancer and 59 normal thyroid tissues were downloaded from the Cancer Genome Atlas database. Thyroid cancer tissues were classified according to the histological type, grouped based on low and high median miR-369-3p and TSPAN13 expression, and analyzed in relation to overall survival (OS) of patients. Human PTC cell lines (TPC-1 and GLAG-66) and human embryonic kidney 293T (HEK293T) cells were used for in vitro analysis. Transfection experiments were performed with synthetic miRNA mimics for miR-369-3p and small interfering RNAs for TSPAN13. Relative expression of miR-369-3p and TSPAN13 mRNA was determined by RT-qPCR. Protein levels of TSPAN13 were determined by western blotting. Cell proliferation (CCK-8 assay), colony formation, and apoptosis (flow cytometry) were analyzed in transfected cells. Binding sites of miR-369-3p in TSPAN13 mRNA were determined by bioinformatics analysis and dual luciferase reporter assay. miR-369-3p was downregulated and TSPAN13 upregulated in PTC, follicular thyroid cancer, and tall cell variant tissues. Both low expression of miR-369-3p and high expression of TSPAN13 were associated with shorter OS in thyroid cancer patients. Overexpression of miR-369-3p significantly suppressed proliferation and promoted apoptosis in PTC cells. TSPAN13 was a direct target of miR-369-3p, and silencing of TSPAN13 phenocopied the effect of miR-369-3p mimics in PTC cells. Overall, the downregulation of miR-369-3p and consequent upregulation of its target TSPAN13 appear to be involved in pathophysiology of PTC.


Adverse childhood experiences: Mechanisms of risk and resilience in a longitudinal urban cohort.
There is an extensive literature describing the detrimental effects of adverse childhood experiences (ACE; e.g., abuse, neglect, and household dysfunction) on physical and mental health. However, few large-scale studies have explored these associations longitudinally in urban minority cohorts or assessed links to broader measures of well-being such as educational attainment, occupation, and crime. Although adversity and resilience have long been of interest in developmental psychology, protective and promotive factors have been understudied in the ACE literature. This paper investigates the psychosocial processes through which ACEs contribute to outcomes, in addition to exploring ways to promote resilience to ACEs in vulnerable populations. Follow-up data were analyzed for 87% of the original 1,539 participants in the Chicago Longitudinal Study (N = 1,341), a prospective investigation of the impact of an Early Childhood Education program and early experiences on life-course well-being. Findings suggest that ACEs impact well-being in low-socioeconomic status participants above and beyond the effects of demographic risk and poverty, and point to possible mechanisms of transmission of ACE effects. Results also identify key areas across the ecological system that may promote resilience to ACEs, and speak to the need to continue to support underserved communities in active ways.


Outcomes 18 years after implementation of a nonoperative caries preventive program--the Nexö-method--on children in Moscow, Russia.
To report the long-term effect (18 years) of the Nexö-method, initially implemented in groups of children in Moscow in 1994. Three groups of children were included in the initial study in 1994. This study is a follow-up study of two of the three initial groups: a group of 6-year-olds (test group6 ; control group6 ) and a group of 11-year-olds (test group11 , control group11) , n = 50 individuals in each of the four subgroups. In 2012, >80% of the participants in the two groups (now aged 24 and 28 years old) were re-examined by the original examiner, who was blinded to which group the patients had belonged in the initial study. After re-examination, the participants were interviewed by a person not otherwise attached to the study. Finally, caries data were collected from 100 24-year-olds and 100 28-year-olds who attended the dental school (50%) and private clinic (50%) in Moscow (External control groups24,28 ). The outcome variables of the study were plaque and gingival status, and DMFT/S. In 2012, the control groups24,28 displayed significantly higher plaque scores than the test groups24,28 (P-values < 0.05). No differences were seen regarding gingivitis scores (P-values > 0.41). Mean DMFT/S in 2012 was test group24 = 6.98/10.51, control group24 = 8.84/13.14 (P = 0.02/0.06). External control group24 = 8.89/15.86 (test24 versus external control group24 , P = 0.01/0.007; control24 versus external control group24 , P = 0.94/0.16). Test group28 = 6.74/10.83, control group28 = 8.70/14.48 (P = 0.02/0.008). External control group28 = 9.03/18.06 (test28 versus external control28 , P = 0.03/0.001; control28 versus external control28 , P = 0.68/0.07). The interview indicated that the participants in the test groups were more aware of factors that are considered important for control of caries than participants in the control groups. The data from this group of Moscow citizens suggest a long-term positive effect of the Nexö-method implemented during childhood.


Herpesvirus saimiri-based gene delivery vectors maintain heterologous expression throughout mouse embryonic stem cell differentiation in vitro.
In order to achieve a high efficiency of gene delivery into rare cell types like stem cells the use of viral vectors is presently without alternative. An ideal stem cell gene therapy vector would be able to infect primitive progenitor cells and sustain or activate gene expression in differentiated progeny. However, many viral vectors are inactivated when introduced in developing systems where cell differentiation occurs. To this end, we have developed a mouse in vitro model for testing herpesvirus saimiri (HVS)-based gene therapy vectors. We demonstrate here for the first time that HVS is able to infect totipotent mouse embryonic stem (ES) cells with high efficiency. We have transduced ES cells with a recombinant virus carrying the enhanced green fluorescent protein (EGFP) gene and the neomycin resistance gene (NeoR) driven by a CMV promoter and the SV40 promoter, respectively. ES cells maintain the viral episomal genome and can be terminally differentiated into mature haematopoietic cells. Moreover, heterologous gene expression is maintained throughout in vitro differentiation. Besides its obvious use in gene therapy, this unique expression system has wide ranging applications in studies aimed at understanding gene function and expression in cell differentiation and development.


Cruveilhier-Baumgarten syndrome without esophageal varices: ultrasonographic diagnosis and echo-Doppler study.
Two cases of Cruveilhier-Baumgarten syndrome not clinically evident and without esophageal varices in patients with liver cirrhosis and portal hypertension are presented. The diagnosis was made by real-time ultrasonography, which showed echographic caput medusae with large afferent umbilical veins and efferent inferior superficial epigastric veins. Doppler flowmetry documented high blood flow rates in these collateral portal-systemic circulations, and this explained the absence of large varices at endoscopy. The role of massive spontaneous portal-systemic shunts in preventing the formation of other shunts and particularly esophageal variceal bleeding is discussed.


[Activation of nucleolar DNA and ribosome biosynthesis in hepatocytes under the effect of glucocorticoids and high density lipoproteins].
The structural bases of cooperative effect of glucocorticoids and HDL brings about the activation of protein biosynthesis in hepatocytes. Using surviving rat liver it was shown that these two compounds together activate the gene expression which was indicated by increased 3H-uridine incorporation into the total RNA pool. The enhanced incorporation of 14C-leucine into proteins in these experiments confirms protein biosynthesis acceleration. With the use of liver perfusion technique it was morphologically demonstrated that the earliest changes in hepatocyte genome take place in nucleoli. The increase of nucleolar dimensions and granular component reflects the activation of ribosomal precursors synthesis. Considerable number of ribosomes in the hepatocyte perinuclear space indicates their active transport across the numerous nuclear membrane pores into the cytoplasm. In the first place and more prominently in hepatocytes the protein synthesis "for export" is stimulated, which was proved by the dynamics of ribosome accumulation on the membranes of endoplasmic reticulum according the perfusion duration. The kupffer cells play a significant role in HDL transcytosis and in the realization of their cooperative effect with glucocorticoids.


Plasticity of rhizosphere hydraulic properties as a key for efficient utilization of scarce resources.
It is known that the soil near roots, the so-called rhizosphere, has physical and chemical properties different from those of the bulk soil. Rhizosphere properties are the result of several processes: root and soil shrinking/swelling during drying/wetting cycles, soil compaction by root growth, mucilage exuded by root caps, interaction of mucilage with soil particles, mucilage shrinking/swelling and mucilage biodegradation. These processes may lead to variable rhizosphere properties, i.e. the presence of air-filled gaps between soil and roots; water repellence in the rhizosphere caused by drying of mucilage around the soil particles; or water accumulation in the rhizosphere due to the high water-holding capacity of mucilage. The resulting properties are not constant in time but they change as a function of soil condition, root growth rate and mucilage age. We consider such a variability as an expression of rhizosphere plasticity, which may be a strategy for plants to control which part of the root system will have a facilitated access to water and which roots will be disconnected from the soil, for instance by air-filled gaps or by rhizosphere hydrophobicity. To describe such a dualism, we suggest classifying rhizosphere into two categories: class A refers to a rhizosphere covered with hydrated mucilage that optimally connects roots to soil and facilitates water uptake from dry soils. Class B refers to the case of air-filled gaps and/or hydrophobic rhizosphere, which isolate roots from the soil and may limit water uptake from the soil as well water loss to the soil. The main function of roots covered by class B will be long-distance transport of water. This concept has implications for soil and plant water relations at the plant scale. Root water uptake in dry conditions is expected to shift to regions covered with rhizosphere class A. On the other hand, hydraulic lift may be limited in regions covered with rhizosphere class B. New experimental methods need to be developed and applied to different plant species and soil types, in order to understand whether such dualism in rhizosphere properties is an important mechanism for efficient utilization of scarce resources and drought tolerance.


The relative benefits of green versus lean office space: three field experiments.
Principles of lean office management increasingly call for space to be stripped of extraneous decorations so that it can flexibly accommodate changing numbers of people and different office functions within the same area. Yet this practice is at odds with evidence that office workers' quality of life can be enriched by office landscaping that involves the use of plants that have no formal work-related function. To examine the impact of these competing approaches, 3 field experiments were conducted in large commercial offices in The Netherlands and the U.K. These examined the impact of lean and "green" offices on subjective perceptions of air quality, concentration, and workplace satisfaction as well as objective measures of productivity. Two studies were longitudinal, examining effects of interventions over subsequent weeks and months. In all 3 experiments enhanced outcomes were observed when offices were enriched by plants. Implications for theory and practice are discussed.


Epstein-Barr virus (EBV) SM protein induces and recruits cellular Sp110b to stabilize mRNAs and enhance EBV lytic gene expression.
Promyelocytic leukemia protein (PML) nuclear bodies or nuclear domain 10s (ND10s) are multiprotein nuclear structures implicated in transcriptional and posttranscriptional gene regulation that are disrupted during replication of many DNA viruses. Interferon increases the size and number of PML nuclear bodies and stimulates transcription of several genes encoding PML nuclear body proteins. Moreover, some PML nuclear body proteins colocalize at sites of viral DNA synthesis and transcription. In this study, the relationship between lytic Epstein-Barr virus (EBV) replication and Sp110b, a PML nuclear body protein, was investigated. Sp110b is shown to physically and functionally interact with the EBV protein SM. SM is expressed early in the EBV replicative cycle and posttranscriptionally increases the level of target EBV lytic transcripts. SM bound to Sp110b via two distinct sites in Sp110b in an RNA-independent manner. SM also specifically induced expression of Sp110b during lytic EBV replication and in several cell types. Exogenous expression of Sp110b synergistically enhanced SM-mediated accumulation of intronless and lytic viral transcripts. This synergistic effect was shown to be promoter independent, posttranscriptional, and the result of increased stabilization of target transcripts. Finally, inhibiting Sp110b expression decreased accumulation of an SM-responsive lytic EBV transcript in EBV-infected cells. These findings imply that SM induces Sp110b expression, binds to Sp110b, and utilizes the recruited Sp110b protein to increase the stability of lytic EBV transcripts, indicating that Sp110b is a component of the cellular machinery that EBV utilizes to enhance lytic EBV replication.