Epigenetic reprogramming in mammals.
Epigenetic marking systems confer stability of gene expression during mammalian development. Genome-wide epigenetic reprogramming occurs at stages when developmental potency of cells changes. At fertilization, the paternal genome exchanges protamines for histones, undergoes DNA demethylation, and acquires histone modifications, whereas the maternal genome appears epigenetically more static. During preimplantation development, there is passive DNA demethylation and further reorganization of histone modifications. In blastocysts, embryonic and extraembryonic lineages first show different epigenetic marks. This epigenetic reprogramming is likely to be needed for totipotency, correct initiation of embryonic gene expression, and early lineage development in the embryo. Comparative work demonstrates reprogramming in all mammalian species analysed, but the extent and timing varies, consistent with notable differences between species during preimplantation development. Parental imprinting marks originate in sperm and oocytes and are generally protected from this genome-wide reprogramming. Early primordial germ cells possess imprinting marks similar to those of somatic cells. However, rapid DNA demethylation after midgestation erases these parental imprints, in preparation for sex-specific de novo methylation during gametogenesis. Aberrant reprogramming of somatic epigenetic marks after somatic cell nuclear transfer leads to epigenetic defects in cloned embryos and stem cells. Links between epigenetic marking systems appear to be developmentally regulated contributing to plasticity. A number of activities that confer epigenetic marks are firmly established, while for those that remove marks, particularly methylation, some interesting candidates have emerged recently which need thorough testing in vivo. A mechanistic understanding of reprogramming will be crucial for medical applications of stem cell technology.


Esterase SeE of Streptococcus equi ssp. equi is a novel nonspecific carboxylic ester hydrolase.
Extracellular carboxylic ester hydrolases are produced by many bacterial pathogens and have been shown recently to be important for virulence of some pathogens. However, these hydrolases are poorly characterized in enzymatic activity. This study prepared and characterized the secreted ester hydrolase of Streptococcus equi ssp. equi (designated SeE for S. equi esterase). SeE hydrolyzes ethyl acetate, acetylsalicylic acid, and tributyrin but not ethyl butyrate. This substrate specificity pattern does not match those of the three conventional types of nonspecific carboxylic ester hydrolases (carboxylesterases, arylesterases, and acetylesterases). To determine whether SeE has lipase activity, a number of triglycerides and vinyl esters were tested in SeE-catalyzed hydrolysis. SeE does not hydrolyze triglycerides and vinyl esters of long-chain carboxylic acids nor display interfacial activation, indicating that SeE is not a lipase. Like the conventional carboxylesterases, SeE is inhibited by di-isopropylfluorophosphate. These findings indicate that SeE is a novel carboxylesterase with optimal activity for acetyl esters.


Indirect measurement of the magnetocaloric effect using a novel differential scanning calorimeter with magnetic field.
A simple and high-sensitivity differential scanning calorimeter (DSC) unit operating under magnetic field has been built for indirect determination of the magnetocaloric effect. The principle of the measuring unit in the calorimeter is based on Peltier elements as heat flow sensors. The high sensitivity of the apparatus combined with a suitable calibration procedure allows very fast and accurate heat capacity measurements under magnetic field to be made. The device was validated from heat capacity measurements for the typical DSC reference material gallium (Ga) and a La(0.67)Ca(0.33)MnO(3) manganite system and the results were highly consistent with previous reported data for these materials. The DSC has a working range from 200 to 340 K and has been tested in magnetic fields reaching 1.8 T. The signal-to-noise ratio is in the range of 10(2)-10(3) for the described experiments. Finally the results have been compared to results from a Quantum Design(R) physical properties measuring system. The configuration of the system also has the advantage of being able to operate with other types of magnets, e.g., permanent magnets or superconducting coils, as well as the ability to be expanded to a wider temperature range.


Protective effects of dietary lactulose and calcium phosphate against Salmonella infection.
Protection against intestinal infections by lactulose fermentation might be enhanced by calcium phosphate, due to the increased buffering capacity and/or inhibition of the cytotoxicity of luminal contents. SPF rats were fed a low-calcium control diet, a low-calcium/lactulose diet or a high-calcium/lactulose diet and orally infected with Salmonella enteritidis. Faeces and urine were sampled for microbiological and chemical analyses. The lactulose-fed rats had a better colonization resistance. Translocation was reduced by dietary calcium, whereas lactulose was ineffective. In addition, calcium supplementation stimulated lactulose fermentation, reversed the lactulose-induced increase in cytotoxicity of faecal water and normalized growth and faecal consistency. The combination of dietary lactulose and calcium phosphate is protective against Salmonella infection.


Nonlinear Strong Coupling by Second-Harmonic Generation Enhancement in Plasmonic Nanopatch Antennas.
Enhanced electromagnetic fields within plasmonic nanocavity mode volumes enable multiple significant effects that lead to applications in both the linear and nonlinear optical regimes. In this work, we demonstrate enhanced second harmonic generation from individual plasmonic nanopatch antennas which are formed by separating silver nanocubes from a smooth gold film using a sub-10 nm zinc oxide spacer layer. When the nanopatch antennas are excited at their fundamental plasmon frequency, a 104-fold increase in the intensity of the second harmonic generation wave is observed. Moreover, by integrating quantum emitters that have an absorption energy at the fundamental frequency, a second order nonlinear exciton - polariton strong coupling response is observed with a Rabi splitting energy of 19 meV. The nonlinear frequency conversion using nanopatch antennas thus provides an excellent platform for nonlinear control of the light-matter interactions in both weak and strong coupling regimes which will have a great potential for applications in optical engineering and information processing.


Berberine Reduces cAMP-Induced Chloride Secretion in T84 Human Colonic Carcinoma Cells through Inhibition of Basolateral KCNQ1 Channels.
Berberine is a plant alkaloid with multiple pharmacological actions, including antidiarrhoeal activity and has been shown to inhibit Cl(-) secretion in distal colon. The aims of this study were to determine the molecular signaling mechanisms of action of berberine on Cl(-) secretion and the ion transporter targets. Monolayers of T84 human colonic carcinoma cells grown in permeable supports were placed in Ussing chambers and short-circuit current measured in response to secretagogues and berberine. Whole-cell current recordings were performed in T84 cells using the patch-clamp technique. Berberine decreased forskolin-induced short-circuit current in a concentration-dependent manner (IC(50) 80 ± 8 μM). In apically permeabilized monolayers and whole-cell current recordings, berberine inhibited a cAMP-dependent and chromanol 293B-sensitive basolateral membrane K(+) current by 88%, suggesting inhibition of KCNQ1 K(+) channels. Berberine did not affect either apical Cl(-) conductance or basolateral Na(+)-K(+)-ATPase activity. Berberine stimulated p38 MAPK, PKCα and PKA, but had no effect on p42/p44 MAPK and PKCδ. However, berberine pre-treatment prevented stimulation of p42/p44 MAPK by epidermal growth factor. The inhibitory effect of berberine on Cl(-) secretion was partially blocked by HBDDE (∼65%), an inhibitor of PKCα and to a smaller extent by inhibition of p38 MAPK with SB202190 (∼15%). Berberine treatment induced an increase in association between PKCα and PKA with KCNQ1 and produced phosphorylation of the channel. We conclude that berberine exerts its inhibitory effect on colonic Cl(-) secretion through inhibition of basolateral KCNQ1 channels responsible for K(+) recycling via a PKCα-dependent pathway.


Impact of surface maintenance on BioSand filter performance and flow.
The BioSand filter (BSF) is a household scaled, intermittently operated, slow sand filter. The BSF requires maintenance to remove trapped sediments. This study evaluated the effects of maintenance on the filter's flow rate and performance. Four concrete BSFs received three styles of maintenance: surface agitation (SA), stirring method (SM), and sand removal (SR). Effluent water was collected from the filter between 0-2 L effluent (0-2 L effluent) and between 15-20 L effluent (15 L+ effluent). After maintenance, effluent at 15 L+ (no pause time) showed a significant decrease in thermotolerant coliform removal rates by 0.66-0.91 log (SA), 0.57-0.67 log (SM) and 0.32-0.83 log (RM) (<0.001). Effluent water at 0-2 L (with pause time) did not significantly decrease in thermotolerant coliform removal rates (>0.17) for any maintenance method. The recovery duration after maintenance for all methods at 0-2 L effluent had a median recovery of <1.2 days. The effluent at 15 L+ had a longer recovery period (at least 3.9, 3.0 and 12.75 days for the SA, SM, and SR method, respectively). The flow rate recovery for SA (76%) and SM (82%) was lower compared to SR (138%).


Prophylactic methylxanthines for endotracheal extubation in preterm infants.
Weaning and extubating preterm infants on intermittent positive pressure ventilation (IPPV) for respiratory failure may be difficult. A significant contributing factor is thought to be the relatively poor respiratory drive and tendency to develop hypercarbia and apnoea, particularly in very preterm infants. Methylxanthine treatment started before extubation might stimulate breathing and increase the chances of successful weaning from IPPV. To determine the effects of prophylactic methylxanthine treatment on the use of intubation and IPPV and other clinically important side effects in preterm infants being weaned from IPPV and in whom endotracheal extubation is planned. The standard search strategy of the Cochrane Neonatal Review Group was used. This included searches of The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 2, 2010), the Oxford Database of Perinatal Trials, MEDLINE (1966 to July 2010), CINAHL (1982 to July 2010) and EMBASE (1988 to July 2010). All published trials utilising random or quasi-random patient allocation in which treatment with methylxanthines (theophylline or caffeine) was compared with placebo or no treatment to improve the chances of successful extubation of preterm or low birth weight infants were included. The standard methods of the Cochrane Collaboration and its Neonatal Review Group were used. Seven studies were identified for inclusion. Methylxanthine treatment results in a reduction in failure of extubation within one week (summary RR 0.48, 95%CI 0.32 to 0.71; summary RD -0.27, 95%CI -0.39 to -0.15; NNT 4, 95%CI 3 to 7; six trials, 172 infants). There is significant heterogeneity in the RD meta-analysis perhaps related to the large variation in baseline rate in the control groups (range 20 to 100%).The CAP trial enrolled the largest number of infants, but did not report extubation rates. In the caffeine group, there were lower rates of bronchopulmonary dysplasia, PDA ligation, cerebral palsy and death or major disability at 18 to 21 months. Infants receiving caffeine had reduced postmenstrual ages at time of discontinuing oxygen therapy, positive pressure ventilation and endotracheal intubation. Methylxanthines increase the chances of successful extubation of preterm infants within one week of age. Important neurodevelopmental outcomes are improved by methylxanthine therapy. In any future trials, there is a need to stratify infants by gestational age (a better indicator of immaturity than birth weight). Caffeine, with its wider therapeutic margin, would be the better treatment to evaluate against placebo.


Measuring the superfluid fraction of an ultracold atomic gas.
We propose a method to measure the superfluid fraction of an atomic gas. The method involves the use of a vector potential generated by optical beams with nonzero angular momenta to simulate uniform rotation. The induced change in angular momentum of the atomic gas can be measured spectroscopically. This allows a direct determination of the superfluid fraction.


[Application of immune cell infiltration in the diagnosis and prognosis of non-small cell lung cancer].
Immune cell infiltration is of great significance for the diagnosis and prognosis of cancer. In this study, we collected gene expression data of non-small cell lung cancer (NSCLC) and normal tissues included in TCGA database, obtained the proportion of 22 immune cells by CIBERSORT tool, and then evaluated the infiltration of immune cells. Subsequently, based on the proportion of 22 immune cells, a classification model of NSCLC tissues and normal tissues was constructed using machine learning methods. The AUC, sensitivity and specificity of classification model built by random forest algorithm reached 0.987, 0.98 and 0.84, respectively. In addition, the AUC, sensitivity and specificity of classification model of lung adenocarcinoma and lung squamous carcinoma tissues constructed by random forest method 0.827, 0.75 and 0.77, respectively. Finally, we constructed a prognosis model of NSCLC by combining the immunocyte score composed of 8 strongly correlated features of 22 immunocyte features screened by LASSO regression with clinical features. After evaluation and verification, C-index reached 0.71 and the calibration curves of three years and five years were well fitted in the prognosis model, which could accurately predict the degree of prognostic risk. This study aims to provide a new strategy for the diagnosis and prognosis of NSCLC based on the classification model and prognosis model established by immune cell infiltration.


The origami of thioredoxin-like folds.
Origami is the Japanese art of folding a piece of paper into complex shapes and forms. Much like origami of paper, Nature has used conserved protein folds to engineer proteins for a particular task. An example of a protein family, which has been used by Nature numerous times, is the thioredoxin superfamily. Proteins in the thioredoxin superfamily are all structured with a beta-sheet core surrounded with alpha-helices, and most contain a canonical CXXC motif. The remarkable feature of these proteins is that the link between them is the fold; however, their reactivity is different for each member due to small variations in this general fold as well as their active site. This review attempts to unravel the minute differences within this protein family, and it also demonstrates the ingenuity of Nature to use a conserved fold to generate a diverse collection of proteins to perform a number of different biochemical tasks.


Follicle-stimulating hormone response to luteinizing-hormone-releasing hormone in patients with hydatidiform mole.
The serum concentration of immunoreactive follicle-stimulating hormone (FSH) and FSH response to synthetic luteinizing-hormone-releasing hormone (LHRH) were investigated in 9 patients with intact hydatidiform moles and 3 patients with aborted moles. The serum concentration of FSH before and after intravenous administration of 200 mug of synthetic LHRH was measured by double antibody radioimmunoassay. Serum FSH was detectable but relatively low compared with the levels seen in the follicular phase of the normal menstrual cycle in all 12 patients. Furthermore, the 12 patients did not respond, or responded subnormally, to exogenously administered LHRH, and there was no significant elevation in serum FSH levels after LHRH injection. The result of the current study is in accord with that of our previous report on the serum concentration of FSH and FSH response to synthetic LHRH during normal pregnancy. Thus, it might be concluded that the follicle-stimulating activity of the anterior pituitary is suppressed by an unknown mechanism during molar pregnancy as well as normal pregnancy.


Comparative study of assays detecting complement activation. Complement-split product C3d (rocket immuno-electrophoresis) and C3d neodeterminants (ELISA).
The aim of the study was to investigate the correlation between two types of assay measuring specific products of complement C3 activation and their clinical application. Complement C3d split product was estimated using double-decker rocket immunoelectrophoresis (DD-RIE) and measurements of C3d neodeterminants exposed after C3 activation was carried out with an enzyme-linked immunosorbent assay (ELISA). A total of 595 blood samples were measured in parallel in the DD-RIE and the ELISA test systems. The samples originated from blood donors (44), uraemic patients undergoing dialysis (135), serial samples from rheumatoid arthritis (RA) patients during steroid treatment (88) and 328 randomly collected patient samples. The mean values for DD-RIE and ELISA (+/- 1 SD) for the 595 samples were 48 (+/- 20) mU/l and 48 (+/- 28) mU/l respectively. The interassay coefficient of variation (CV) in the ELISA was 18%. The Spearman rho-correlation coefficient between the two assays was 0.63 for all 595 samples. The mean values using ELISA and DD-RIE were practically identical for the 328 successively incoming samples, the samples from the 135 dialysis patients and the 44 donors. In RA patients a higher mean value was found for the 88 samples using DD-RIE than ELISA. In the majority of patient samples there was a good correlation between the two assays. However, the ELISA appears to be more sensitive in detecting acute complement activation and to give lower levels in RA patients with chronic complement activation.


Thermally changing lattice distance of lamella in the hydrated solid of octadecyltrimethylammonium chloride.
A temperature scanning small-angle X-ray scattering measurement was carried out for the hydrated solids of octadecyltrimethylammonium chloride (OTAC). A gradual change of the lattice spacing of lamella-like structure from 40 nm at 5 degrees C to 20 nm at 18 degrees C was observed in the melting process of the hydrated solid that was incubated at 4 degrees C for a period of 24 h in the aqueous solution, while little change of the lattice spacing of about 20 nm was observed in the same process of the hydrated solid that was incubated at 4 degrees C for a period about 10 min. This indicates structural changes of the hydrated solid during the incubation at 4 degrees C and in the melting process. Corresponding to the nanostructure changes, broad endothermic peaks were observed at temperatures from 13 to 22 degrees C for the former hydrated solid and at temperatures from 15 to 21 degrees C for the latter hydrated solid in difference scanning calorimetry measurements. The structure change at temperatures below 13 degrees C is considered to be athermal from the fact that no endothermic peak is observed there. Large dielectric dispersions at frequencies at about 10 kHz were observed for the suspensions of hydrated solids but not for the solutions of dissolved solids. It was found that the electric conductance of the hydrated solid suspensions was much lower than that of the solutions of dissolved solids. The observed electric properties indicate that an amount of the free chloride ion is very small and that the chloride ions binding to the ammonium groups are movable in the hydrated solids by responding to an applied electric field. The electric conductance of suspension of the hydrated solid being incubated at 4 degrees C for 10 min was 4 times as large as that of a suspension of the hydrated solid being incubated at the same temperature for 24 h. This indicates that the structural change of the OTAC hydrated solid at 4 degrees C is related to the chloride ion binding to the hydrated solid. The experimental results described above suggest that the lamella in the hydrated solid of OTAC is undulated and that the wavelength of undulation increases with the incubation at a temperature much lower than the melting temperature.


Equine influenza A(H3N8) virus infection in cats.
Interspecies transmission of equine influenza A(H3N8) virus has resulted in establishment of a canine influenza virus. To determine if something similar could happen with cats, we experimentally infected 14 cats with the equine influenza A(H3N8) virus. All showed clinical signs, shed virus, and transmitted the virus to a contact cohort.


Late-Developing Metastatic Malignant Melanoma in the Thoracic Spine Originating from Choroidal Melanoma.
A 54-year-old woman visited Gangnam Severance Hospital for left side flank pain. She had a history of total removal of malignant melanoma on the left eye ball 20 years prior. No evaluation had been performed since then. A paravertebral mass at thoracic ninth level (T9) was discovered on spinal magnetic resonance imaging, and pathology confirmed malignant melanoma. Following positron emission tomography-computed tomography, no other metastasis was discovered. After removal of the paravertebral mass, palliative chemotherapy (dacabarzine + tamoxifene) was administered in 3 cycles over 2 months. Radiotherapy with simultaneous integrated boost technique was performed at 4,350 cGy total over 15 days, 290 cGy per delivery, and was administered with the first cycle of palliative chemotherapy. Despite this treatment, multiple metastases developed throughout her body 7 months later, and the patient is continuing chemotherapy.


Child sexual abuse evaluations: the scientist-practitioner model.
The scientist-practitioner model is presented as a format for conducting child sexual abuse evaluations. This model bases conclusions on empirically established relationships between data and the behavior of interest, rather than on subjective opinions. Using empirically derived evidence, the scientist-practitioner defines child sexual abuse as a life event rather than a clinical syndrome, relies on base rates of behavior for distinguishing and understanding differences between nonsexually abused and sexually abused children, and considers issues of instrument sensitivity and specificity when utilizing assessment tools in child sexual abuse evaluations. This model enlists safeguards to keep the evaluator from inappropriately forming cause and effect associations between a child's single response (e.g., behavioral and emotional symptoms, interactions with anatomically detailed dolls, drawing genitalia) and the occurrence of an event (e.g., sexual abuse).


Analysis of persistent organic pollutants at sub-femtogram levels using a high-power picosecond laser for multiphoton ionization in conjunction with gas chromatography/time-of-flight mass spectrometry.
A low-energy, high-repetition-rate picosecond laser (40 µJ, 20 kHz, 258 nm) was used for multiphoton ionization (MPI) in gas chromatography/time-of-flight mass spectrometry to quantitatively determine dioxins (DXNs) and polycyclic aromatic hydrocarbons (PAHs). The sensitivity of the technique was compared with that obtained using a high-energy, low-repetition-rate femtosecond laser (86 µJ, 1 kHz, 261 nm). The limits of detection (LODs) for the picosecond laser were several femtograms for chlorinated DXNs with low numbers of chloro substituents, and were several times lower than values obtained using a femtosecond laser, although the LODs were increased, reaching values that were nearly identical to those for the femtosecond laser for octachlorodibenzo-p-dioxin (octaCDD) and octachlorodibenzofuran (octaCDF). The LODs were also measured for 16 PAHs specified by the United States Environmental Protection Agency; the values for half of these compounds were at sub-femtogram levels. The procedure was used to analyze a surface-water sample collected from a river.


ALLOZYME DIVERSITY AND GENETIC IDENTITY IN SCHIEDEA AND ALSINIDENDRON (CARYOPHYLLACEAE: ALSINOIDEAE) IN THE HAWAIIAN ISLANDS.
Genetic diversity of allozymes, genetic identity based on allozyme variability, and phylogenetic relationships were studied with respect to breeding system diversity, population size, and island age in 20 of the 29 species of Schiedea and Alsinidendron (Caryophyllaceae: Alsinoideae), a monophyletic lineage endemic to the Hawaiian Islands. Average levels of genetic variability in Schiedea and Alsinidendron were comparable to or higher than those found in other Hawaiian lineages for which equivalent data are available [Bidens, Tetramolopium, and the silversword alliance (Asteraceae: Madiinae)] and similar to average values for species of dicots. Allozyme variability was strongly dependent on breeding system, which varies widely in the Hawaiian Alsinoideae. Species with autogamous breeding systems showed very low variability, measured as the number of alleles per locus, percent polymorphic loci, and mean heterozygosity per locus. Outcrossing hermaphroditic and dimorphic species (those with gynodioecious, subdioecious, and dioecious breeding systems) showed significantly higher genetic variability. Small population size was associated with lower values for all measures of genetic variability. Nearly half of the species occurring in small populations are also autogamous; thus, both factors may have influenced levels of genetic variability in these species. Founder effect was apparent in one species (Schiedea adamantis), which occurs in a single large population, has a gynodioecious breeding system but a very low genetic variability. Island age appeared to have little effect on genetic variability. Slightly lower values of genetic variability for species occurring on Kaua'i and O'ahu result primarily from the occurrence of autogamous Alsinidendron species on those islands. Values for Nei's genetic identity for different species pairs were 0.201-0.942, a far greater range than in Bidens, the silversword alliance, and Tetramolopium. Using UPGMA clustering, there was only moderate support for relationships detected through cladistic analysis. Nei's unbiased genetic identity (I) was greatest among species with outcrossing breeding systems, which for the most part clustered together. Nei's genetic identities for self-fertilizing species were low, indicating that these species are less similar to one another and to outcrossing species, regardless of their affinities based on cladistic analysis. Parsimony analysis of allele frequency data supported two clades also found in phylogenetic analyses using morphological and molecular data. Clades recognized in parsimony analysis of allele frequencies were those lineages containing selfing species, indicating that conditions favoring fixation of alleles occurred in ancestral species. In contrast, maintenance of high genetic diversity in outcrossing species interferes with recognition of phylogenetic relationships using allozyme variability.


[Stress sensitivity and adaptation].
On the basis of theoretical, clinical and experimental analyses the influence of different stress categories, especially of psycho-emotional and socio-emotional stress, upon cerebro-visceral regulation processes is investigated. Central-nervous information processing in various brain areas (neocortex, limbic system, hypothalamus, formatio reticularis mesencephali etc.) and learning processes are equally affected by stress factors as are haemodynamic and biochemical parameters. Changes of the carbohydrate and lipid metabolism, of plasma renin activity, catechol amine release and the counter-regulatory insulin enhancement are especially pronounced in "stress-sensitive risk persons", e.g. in the hypertensive as a maladaptive dysregulation-as opposed to the adaptive regulation capacity of healthy individuals. The investigated functional patterns of different systems of the organism allow the distinction of hyper- and hyporeactive forms of maladaptation. The pathogenetic efficiency of stress is determined not only by the quantity, quality, duration of exposure and basic processes of the central nervous system, but also by man's personality structure and his sensitivity to stress (genetic predisposition and/or acquired maladaptation). More insight into the neuro-biological processes underlying the motivational and psycho-emotional performance of the brain and its connection withe humoral-hormonal and cardiovascular systems is necessary to treat and to control cerebrovisceral dysregulations such as arterial essential hypertension. It will be a task of psychotherapy to help improve man's adaptive capacity and to desensibilize stress-sensitive risk persons.


Treatment of Adults with Anterior Mandibular Teeth Crowding: Reliability of Little's Irregularity Index.
The attempt of this article was to assess reliability of Little's Irregularity Index (LII) as for stability of the treatment outcomes in adults with crowded mandibular incisors. LII was measured on a digital cast prior to an orthodontic treatment (T1) of the 302 patients thus allowing us to establish the treatment plan, which called for (a) expansion (group 1), interproximal stripping (group 2), or extraction of one of the mandibular incisors. LII was measured after debonding (T2) and a year after retention (T3). Treatment resulted in significant reduction of LII values after treatment, in T1-T2 period in all groups. As for T2-T3 period it brought significant but clinically irrelevant relapse that occurred in groups 1 and 2; group 3 presented with insignificant improvement of occlusion. Conclusively, 30 years after introducing LII it has been a reliable parameter that allows selection of optimal treatment methods, provided that the appropriate ranges of values displaying dentoalveolar discrepancy are obeyed, namely, (1) up to 3 mm: expansion, (2) from 3 to 5 mm: interproximal enamel reduction, and (3) above 5 mm: extraction.


Perceived uncertainty, coping strategies, and adaptation in women with human papillomavirus on pap smear.
To explore, identify, and describe the perception of uncertainty over time in college-aged women experiencing the unexpected event of an abnormal Pap smear with human papillomavirus (HPV). Eighty-eight female patients, who had abnormal Pap smear and had indications for colposcopy, were recruited from a Student Health Service and consented for study participation. Uncertainty levels were measured over time. Relationships among uncertainty, knowledge of HPV, body attitude and moods, coping strategies, and follow-up were evaluated. The relationship between uncertainty and coping strategies was supported in the emotion-focused path as predicted but not in the problem-focused path. Evidence of adaptation to uncertainty through emotion-focused coping was found in the significant relationship between emotion-focused coping and body attitude. Similarly, there was a significant relationship between emotion-focused coping and moods in the path analysis and in correlations with the subcategories of positive and negative moods. The problem-focused indirect path from uncertainty to adaptation showed no significant relationship. Likewise, uncertainty also had no significant direct effect on body attitude or promptness of follow-up but did have a direct impact on moods. The direct path from previous knowledge to uncertainty was not supported. The presence of uncertainty over time was established in this study population. Statistically significant relationships were confirmed among uncertainty, emotion-focused coping strategies, and adaptation in a group of young women experiencing a mildly abnormal Pap smear.


Are the associations between life-style related factors and plasma total homocysteine concentration different according to polymorphism of 5,10-methylenetetrahydrofolate reductase gene (C677T MTHFR)? A cross-sectional study in a Japanese rural population.
Mild hyperhomocysteinemia is one of the known strong risk factors for atherosclerotic diseases, and therefore it is important to clarify factors that could determine plasma total homocysteine (tHcy) level. A cross-sectional study with a random sample of 455 Japanese rural residents aged 40-69 years was conducted in 2000 to investigate the associations of plasma tHcy concentration with 5,10-methylenetetrahydrofolate reductase (MTHFR) gene and selected life-style related factors. The frequency of the mutant allele, Valine (V) allele, was 0.40 and the prevalence of VV genotype was 14.3%. Plasma tHcy concentration in VV was significantly higher than those in two other genotypes. There were significant inverse associations of plasma tHcy with serum folate and serum vitamin B12 (P<0.001 for trend, respectively); both being stronger in VV than in other genotypes. The number of cigarettes smoked per day was positively associated with plasma tHcy concentration. A multivariate regression analysis revealed that serum folate, serum vitamin B12, and MTHFR genotype were independently associated with plasma tHcy. The inter-individual variance of plasma tHcy was more explained by serum folate and vitamin B12 than by MTHFR genotype. Higher intakes of folate, vitamin B12, and non-smoking may be important to prevent mild hyperhomocysteinemia and the eventual atherosclerotic diseases in this Japanese rural population.


The anti-tumor potential of sinomenine: a narrative review.
Currently, chemotherapy is the main treatment for most tumors. However, drug resistance and many adverse reactions associated with chemotherapy greatly limit its use. Therefore, an increasing number of researchers have shifted the research focus the anti-tumor activity of traditional Chinese medicine. The objective of this article is to review the anti-tumor mechanism of sinomenine and its derivatives to provide a reference for further study and clinical transformation. In this study, we searched for relevant articles on the anti-tumor mechanism of Sinomenium using databases such as PubMed and Medline. Sinomenine is a monomer alkaloid component extracted from the rhizome of Sinomenium acuturn. A number of basic studies have proven that sinomenine and its derivatives show significant anti-tumor activity in breast cancer, lung cancer, liver cancer, stomach cancer, ovarian cancer, osteosarcoma and other tumors. They can induce apoptosis and autophagic death of tumor cells, inhibit proliferation, migration and invasion of tumor cells, increase the sensitivity of tumor cells to radiotherapy and chemotherapy, and reverse the drug resistance through various molecular mechanisms. In addition, sinomenine can effectively relieve osteolysis and bone pain in tumor patients. At present, anti-tumor research on sinomenine remains in the basic experimental stage. Sinomenine and its derivatives are rich in substances with high anti-tumor potential. This analysis provides a review of the anti-tumor effects and mechanisms of sinomenine, with the hope of further exploring the medical value of sinomenine in anti-tumor treatments.


Oxidative cross-coupling/cyclization to build polysubstituted pyrroles from terminal alkynes and β-enamino esters.
A novel silver-mediated highly selective synthesis of polysubstituted pyrroles by the C-H/C-H oxidative cross-coupling/cyclization of terminal alkynes with β-enamino esters has been developed. This protocol represents a simple, efficient and selective way to construct polysubstituted pyrroles in good yields from basic chemical materials.


Do people perceive benefits in the use of social prescribing to address loneliness and/or social isolation? A qualitative meta-synthesis of the literature.
Social prescribing is a means by which clinical services can link individuals who have psychological, social and/or practical needs with non-clinical services within their local community. There is a lack of empirical evidence investigating whether social prescribing helps such individuals and which interventions are the most effective and accepted by them to address their loneliness. This meta-synthesis aimed to synthesise findings from qualitative studies exploring experiences of people (of any age) who participated in any social prescribing intervention aimed at loneliness and/or social isolation to ascertain whether they felt it helped address loneliness/isolation and the potential mechanisms by which this might occur. We conducted a systematic search of 5 electronic databases and 4 other databases that would yield grey literature in April 2021 to identify qualitative articles on this topic written in English or French. We assessed the quality of the included studies using recognised tools, and synthesised findings using the approach of thematic analysis. We identified 19 records analysed (e.g. journal articles) from 18 studies meeting inclusion criteria. Our analysis identified three themes: (1) increased sense of wellbeing (with six subthemes), (2) factors that engendered an ongoing desire to connect with others, and (3) perceived drawbacks of social prescribing. These themes illustrate the benefits and difficulties people perceive in social prescribing programmes addressing loneliness and social isolation, with an overall balance of more benefits than drawbacks in social prescribing participation. However, given the unhelpful aspects of social prescribing identified by some participants, greater thought should be given to potential harms. Moreover, further qualitative and quantitative research is needed to better understand mechanisms and effectiveness, and how different components of social prescribing might be best matched to individual participants.


Combined effects of long-pulsed neodymium-yttrium-aluminum-garnet laser, diprospan and 5-fluorouracil in the treatment of keloid scars.
Keloids are benign tumors that originate from scar tissues, but they usually overgrow beyond the original wounds. In a three-month single-center clinical trial, 69 patients were randomly divided into three groups. Patients in group 1 were treated with intralesional injection of diprospan (2 mg betamethasone disodium phosphate and 5 mg betamethasone dipropionate in 1 ml) with one-month intervals for three months. Patients in groups 2 and 3 were injected with a combination of 0.5 ml 5-fluorouracil (5-FU; 25 mg/ml) and diprospan as above for three months also. Prior to each injection, the keloids of patients in group 3 were additionally irradiated by a 1,064-nm neodymium-yttrium-aluminum-garnet (Nd:YAG) laser with a single pulse at an energy density of 90-100 J/cm2 and a pulse width of 12 msec. Clinical responses were evaluated by patient self-assessment and overall assessment by an observer according to the clinical signs of erythema, pruritus and pliability. A total of sixty-two patients completed the tests of the present study. At 2 and 3 months, the patients in all treatment groups showed an acceptable improvement in nearly all measurements. At the end of the study, the erythema and toughness score was significantly reduced and itch reduction was significantly greater in the diprospan + 5-FU + Nd:YAG group when compared to those in the other groups (P<0.05 for all indexes). The acceptable responses (good to excellent improvements) reported by blinded observers were as follows: 12% in the diprospan group, 48% in the diprospan + 5-FU group and 69% in the diprospan + 5-FU + Nd:YAG group. All of the results indicated that the combination of diprospan + 5-FU + Nd:YAG was the most efficacious therapy for keloid scars.


Turbidimetric measurement of total urinary proteins: a revised method.
A turbidimetric method for the determination of total urinary proteins is proposed that uses a specimen blank for each urine. The precipitant, trichloroacetic acid (TCA), is introduced into the blank and the sample in the same amount. The blank is the supernatant of the TCA-treated urine for each specimen. Turbidity is measured by reading the 420-nm absorbance 35 minutes after the TCA addition when the turbidity curves for most urine samples plateau. This improved method was compared with an established procedure that uses water to prepare the blanks and that measures turbidity 5 minutes after the TCA addition. Of the 69 urine specimens that were analyzed by the two methods, the revised procedure yielded higher values (greater than or equal to 150%) for 5 samples, while 21 samples had lower values (less than or equal to 50%). In the latter group, four cases would have been classified erroneously as having significant proteinuria by the established method.


Platycodin D protects against cigarette smoke-induced lung inflammation in mice.
Cigarette smoke is the one of the major factors that leads to chronic obstructive pulmonary disease (COPD). Inflammation and oxidant stress have been known to play critical roles in the development of COPD. Platycodin D (PLD) has been reported to have anti-inflammatory and anti-oxidant effects. In this study, we aimed to investigate the protective effects of PLD on cigarette smoke (CS)-induced lung inflammation in mice. PLD was adminstrated i.p. to mice 2h before CS exposure daily for five consecutive days. The production of inflammatory cytokines TNF-α and IL-1β were measured by ELISA. The levels of malonaldehyde (MDA) and nitric oxide (NO) were also detected in this study. The expression of nuclear factor-erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), NF-κB, and IκBα were detected by western blot analysis. The results showed that PLD significantly attenuated CS-induced lung pathological changes, inflammatory cells infiltration, as well as TNF-α and IL-1β production. CS-induced MDA and NO production were also inhibited by treatment of PLD. Western blot analysis showed that PLD significantly suppressed CS-induced NF-κB activation. In addition, PLD was found to increase the expression of Nrf2 and HO-1. Taken together, these results indicated that PLD protected against CS-induced lung inflammation by inhibiting inflammatory and oxidative response through activating Nrf2 signaling pathway. PLD might be an effective treatment for CS-induced lung inflammation.


Prevalence of Maternal Hepatitis C Virus Infection in Ohio.
To quantify the rising prevalence of maternal hepatitis C virus (HCV) infection in Ohio during the peak of the opioid epidemic and to identify maternal characteristics and obstetric outcomes associated with maternal HCV infection. We conducted a population-based retrospective cohort study of all live births in Ohio (2006-2015). Frequency of maternal HCV infection as reported on birth certificates was compared across each year of the study period. Maternal, obstetric, and neonatal characteristics were compared between women with HCV infection in pregnancy with those without HCV infection. Multivariate logistic regression estimated the relative association between HCV infection and various maternal characteristics and obstetric outcomes. During the 10-year study period, there were 7,069 reported cases of maternal HCV infection at the time of delivery among 1,463,506 (0.5%) live births in Ohio. The rate of maternal HCV infection increased 631% between 2006 and 2015, from 1.6 to 11.7 cases per 1,000 live births (relative risk [RR] 7.6, CI 6.6-8.7, P<.001). After adjusting for various confounders, demographic characteristics associated with HCV infection included cigarette smoking (adjusted RR 8.6, CI 8.0-9.1), Medicaid insurance (adjusted RR 3.6, CI 3.3-3.8), and white, non-Hispanic race (adjusted RR 3.2, 95% CI 2.9-3.5). Coinfection during pregnancy with hepatitis B, gonorrhea, chlamydia, syphilis, and herpes simplex virus infection was also associated with maternal HCV infection. Obstetric and neonatal outcomes associated with maternal HCV infection included cesarean delivery, fetal intolerance of labor, preterm birth, maternal intensive care unit admission, blood transfusion, small for gestational age (less than the 10th percentile), neonatal intensive care unit admission, need for assisted neonatal ventilation, and infant death. Maternal HCV infection has increased more than sevenfold over the past decade in Ohio. Our findings highlight a dramatic rise in maternal HCV infection that parallels the opioid epidemic within Ohio and in neighboring Appalachian states.


A generalization of functional clustering for discrete multivariate longitudinal data.
This paper presents a new model-based generalized functional clustering method for discrete longitudinal data, such as multivariate binomial and Poisson distributed data. For this purpose, we propose a multivariate functional principal component analysis (MFPCA)-based clustering procedure for a latent multivariate Gaussian process instead of the original functional data directly. The main contribution of this study is two-fold: modeling of discrete longitudinal data with the latent multivariate Gaussian process and developing of a clustering algorithm based on MFPCA coupled with the latent multivariate Gaussian process. Numerical experiments, including real data analysis and a simulation study, demonstrate the promising empirical properties of the proposed approach.


Advances in food crystallization.
Crystals often play an important role in food product quality and shelf life. Controlling crystallization to obtain the desired crystal content, size distribution, shape, and polymorph is key to manufacturing products with desired functionality and shelf life. Technical developments in the field have improved the tools with which we study and characterize crystals in foods. These developments also help our understanding of the physico-chemical phenomena that govern crystallization and improve our ability to control it during processing and storage. In this review, some of the more important recent developments in measuring and controlling crystallization are discussed.


Correlation of mast cells with spindle cell hyperplasia in the adrenal cortex of IQI/Jic mice.
IQI/Jic mice showed a high incidence of subcapsular spindle cell hyperplasia (SCH) in the adrenal cortex accompanied by prominent mast cell infiltration. SCH-positive animals appeared as early as at 3 months of age, with an incidence of 18% in males and 20% in females. Except for one mouse, all females older than 6 months had the lesion. In males, the incidence increased gradually until 9 months, and was then stable at 75-88% thereafter. The severity of SCH increased with age in both sexes, and the lesions were more prominent in females. Mast cells infiltrated mainly at the sites of spindle cell hyperplasia, and their density was associated with the severity on the lesion. A quantitative morphometric study confirmed a significant correlation between the severity of SCH and the density of mast cells. A histochemical study demonstrated that these mast cells were of the connective tissue-type. These observations indicate that IQI/Jic mice may be a useful strain to elucidate the pathogenesis of SCH in the adrenal cortex in association with mast cell function.


Evidence for time-dependent activation of monocytes in the systemic circulation in unstable angina but not in acute myocardial infarction or in stable angina.
Platelet activation plays a pivotal role in the pathogenesis of acute coronary disease. Monocytes are involved in the progression of atherosclerosis and are potent activators of blood coagulation through their ability to synthesize tissue factor (TF). The aim of this study was to compare markers of monocyte and coagulation activation in the systemic blood of patients with unstable angina, acute myocardial infarction, or stable angina. We studied 26 patients with unstable angina (10 +/- 5 hours after the onset of the last episode of pain), 18 patients with acute myocardial infarction (5 +/- 4 hours after the onset of pain), and 34 patients with stable angina. We measured levels of TF expression in peripheral blood mononuclear cells (isolated by gradient centrifugation and incubated for 16 hours, with or without endotoxin stimulation), levels of plasma prothrombin fragment 1 + 2 (F1 + 2), and levels of fibrinogen in peripheral blood. In patients with unstable angina, both stimulated and unstimulated cells exhibited higher levels of TF expression than in patients with stable angina (P = .0001). In patients with acute myocardial infarction, monocyte TF activity did not differ from that in patients with stable angina. Mean levels of F1 + 2 and of fibrinogen did not differ significantly between groups. Only in the unstable angina group, a modest correlation was found between fibrinogen (r = .72, P = .005) and F1 + 2 levels (r = .54, P = .001) levels and the degree of monocyte TF expression. In patients with unstable angina, monocyte TF expression (both stimulated and unstimulated, assessed by biological activity and by antigen techniques) and fibrinogen levels were correlated with the time elapsed from the beginning of the most recent episode of pain (.61 < r < .72, .02 < P < .0001). By contrast, there was no correlation between these variables and the time from onset of pain in patients with acute myocardial infarction. A time-dependent activation of systemic monocytes and a time-dependent increase in fibrinogen levels occurs in unstable angina but not in myocardial infarction. These findings provide further evidence that a specific inflammatory process occurs in unstable angina. Further studies are required to determine whether monocyte activation is a cause or a consequence of plaque instability in patients with unstable angina and to clarify the interrelations between platelet and monocyte activation in these circumstances.


Etiology of Diarrhea Requiring Hospitalization in Bangladesh by Quantitative Polymerase Chain Reaction, 2014-2018.
Diarrhea remains a major public health problem and characterization of its etiology is needed to prioritize interventions. However, most data are from single-site studies of children. We tested samples from participants of any age from 11 geographically diverse hospitals in Bangladesh to describe pathogen-specific burdens of diarrhea. We utilized 2 existing diarrhea surveillance systems: a Nationwide network at 10 sentinel hospitals and at the icddr,b hospital. We tested stools from enrolled participants and nondiarrheal controls for enteropathogens using quantitative polymerase chain reaction and calculated pathogen-specific attributable fractions (AFs) of diarrhea. We analyzed 5516 patients with diarrhea and 735 controls. Overall, rotavirus had the highest attributable burden of diarrhea (Nationwide AF, 17.7%; 95% confidence interval [CI], 14.3-20.9%; icddr,b AF, 39.9%; 38.0-41.8%), followed by adenovirus 40/41 (Nationwide AF, 17.9%; 95% CI: 13.9-21.9%; icddr,b AF, 16.6%; 95% CI, 14.4-19.4%) and Vibrio cholerae (Nationwide AF, 10.2%; 95% CI, 9.1-11.3%; icddr,b AF, 13.3%; 95% CI: 11.9-15.1%). Rotavirus was the leading pathogen in children <5 years and was consistent across the sites (coefficient of variation = 56.3%). Adenovirus 40/41 was the second leading pathogen in both children and adults. Vibrio cholerae was the leading pathogen in individuals >5 years old, but was more geographically variable (coefficient of variation = 71.5%). Other attributable pathogens included astrovirus, norovirus, Shigella, Salmonella, ETEC, sapovirus, and typical EPEC. Rotavirus, adenovirus 40/41, and V. cholerae were the leading etiologies of infectious diarrhea requiring hospitalization in Bangladesh. Other pathogens were important in certain age groups or sites.


Bully-Victims: An Analysis of Subtypes and Risk Characteristics.
Bully-victims are often found to be the most high-risk group involved in bullying, yet limited prior research has explored differences among bully-victims. This study aims to fill that gap by exploring within-group differences of youth involved in both bullying perpetration and victimization. In a nationally representative sample of 165 youth ages 5 to 17, four bully-victim types were created using cutoff points based on the amount of perpetration and victimization reported: high bully-victims (n = 38), aggression predominant bully-victims (n = 67), victimization predominant bully-victims (n = 23), and moderate bully-victims (n = 37). Analyses revealed distinct differences among the groups, particularly relating to traumatic symptoms, types of bullying involvement, and nonvictimization adversity. The findings confirm that there is heterogeneity among bully-victims. The most substantial difference was found between the high group and the moderate group, with the high group significantly more likely to report depression (p < .05) and anxiety symptoms (p < .05), and more than two times more likely to experience past-year adversity than the moderate group. The findings from this study indicate that youth involved in high amounts of both perpetration and victimization are considerably more at risk of traumatic symptoms and nonvictimization adversity than youth involved in fewer bullying behaviors. These findings can be used to inform both research and practice, particularly in regard to targeted evidence-based interventions that meet the unique needs of each type.


Survival Rate of Colorectal Cancer in Iran: A Systematic Review and Meta-Analysis
Background: Different studies have been conducted to estimate the survival rate of colorectal cancer in Iran but there is no overall estimate of the survival rate. The aim of this study was to calculate the pooled 1, 3, and 5-year survival rate of the patients with colorectal cancer in Iran. Methods: To retrieve relevant studies, we conducted a systematic search in Iranian databases, including Iran Medex, Magiran, SID, and international databases such as Medlin/PubMed, Scopus, and Google scholar using "Colorectal Neoplasms" and "Survival Rate" as keywords up to December 1st, 2017. We used random effect model to estimate pooled 1, 3, and 5-year survival rates of the patients with colorectal cancer in Iran. To assess the heterogeneity, we used Chi-squared test at the 5 % significance level (p <0.05) and I2 Index. We used meta-regression and subgroup analysis to find a potential source of heterogeneity. Results: After a systematic search, 196 articles were found, of the 38 studies met the eligibility criteria and are included in our meta-analysis. The pooled 1, 3, and 5-year survival rates in patient with colorectal cancer were 0.84 (95% CI: 0.81-0.87), 0.64 (95%CI: 0.59-0.70), and 0.54 (95%CI: 0.49-0.58) respectively. The 5-year survival rate in the subgroup of women was 0.5 (0.44-0.56) and in male subgroup was 0.44 (0.40-0.48). In a subgroup of the tumor site, the 5-year survival rate in colon cancer was 0.6 (0.49-0.75) and rectum cancer was 0.54 (0.36-0.69). In multivariable models, there was a significant association between years of study and 5-year survival rate as a source of heterogeneity (β = 18.9, P=0.01). Conclusion: According to the results of this study, women had a better survival rate than men, and according to the tumor site, the 5-year survival rate in colon cancer was better than the rectum cancer.


Supraclavicular artery island flap for head and neck reconstruction.
The ablative surgical resection has a critical importance for achieving better oncological outcomes for patients with head and neck cancer. However, radical surgical resections reveal the reconstruction requirement of complex anatomical structures. Microvascular free flaps have been recommended as a gold standard treatment choice for head and neck reconstruction following definitive oncological surgery. The supraclavicular artery island flap (SCAIF) is a thin and reliable fasciocutaneous pedicled flap that is simple and quick to harvest. A total of 19 patients who underwent head and neck reconstruction with SCAIF were included in this study. The SCAIF was used for the reconstruction of oncological defects in 17 patients while it was used for the reconstruction of a skin defect on the lower face following radiotherapy in 1 patient and for cervical open wound (blast injury) closure in 1 patient. There were neither intraoperative nor postoperative major complications in any patient. The SCAIF has been used successfully in 18 of 19 patients for head and neck reconstructive surgery. Partial necrosis of the skin was detected in 1 patient (5.3%) only, while a total flap failure has not occurred in any patient. The partial skin necrosis was seen in an area of 1.5 cm of the distal end of the flap and was managed conservatively with local wound care. Wound dehiscence has not appeared in the flap donor area in any patient. The SCAIF constitutes a good alternative to free flaps, providing almost equivalent functional results and requiring less operative time and surgical effort.


Philippine law on donations of human organs.
The Philippines "Organ Donation Act of 1991" updates the "1949 Act to legalize permissions to use human organs". Under the new legislation, each individual can donate all or any part of his body by way of legacy or will. The members of the family may also authorize such a donation in the absence of contrary intention by the decedent. Donations are only valid when made for therapy, research or medical education. International sharing of organs is recognized but subject to approval by the Department of Health. Regulations are about to be formulated in order to implement the Act which will be largely publicized to encourage donations.


MicroRNA-497 acts as a tumor suppressor in gastric cancer and is downregulated by DNA methylation.
Gastric cancer (GC) is one of the most common malignant tumors in the world and microRNAs (miRNAs) play an important role in GC. In this study, we found miR‑497 played an important role and served as a novel biomarker in GC. Quantitative real-time PCR (qRT-PCR) was used to measure the miR‑497 expression in GC cell lines and 86 paired GC samples and we also analyzed its correlation with GC clinicopathological parameters. A series of cellular function experiments were applied to validate the effects of miR‑497 on GC. In addition, methylation-specific PCR (MSP) was applied to detect the gene methylation status. Finally, the correlation between miR‑497 and the target gene was analyzed by western blotting assay. miR‑497 was reduced obviously in GC cells and tissues and significantly associated with the pathologic stage. Low expression of miR‑497 significantly inhibited the proliferation, invasion and migration of GC cell lines and accelerated apoptosis. Moreover, we found that the aberrant expression of miR‑497 may be ascribed to DNA methylation. microRNA.org and luciferase reporter assay suggested that RAF1 was a direct target of miR‑497 in GC. This study suggested that miR‑497 could serve as a tumor suppressor and a potential early diagnostic marker of GC by targeting Raf-1 proto-oncogene, serine/threonine kinase (RAF1).


Gestation under chronic constant light leads to extensive gene expression changes in the fetal rat liver.
Recent reports account for altered metabolism in adult offspring from pregnancy subjected to abnormal photoperiod, suggesting fetal programming of liver physiology. To generate a pipeline of subsequent mechanistic experiments addressing strong candidate genes, here we investigated the effects of constant gestational light on the fetal liver transcriptome. At 10 days of gestation, dams were randomized in two groups (n = 7 each): constant light (LL) and normal photoperiod (12 h light/12 h dark; LD). At 18 days of gestation, RNA was isolated from the fetal liver and subjected to DNA microarray (Affymetrix platform for 28,000 genes). Selected differential mRNAs were validated by quantitative PCR (qPCR), while integrated transcriptional changes were analyzed with Ingenuity Pathway Analysis and other bioinformatics tools. Comparison of LL relative to LD fetal liver led to the following findings. Significant differential expression was found for 3,431 transcripts (1,960 upregulated and 1,471 downregulated), with 393 of them displaying ≥ 1.5-fold change. We validated 27 selected transcripts by qPCR, which displayed fold-change values highly correlated with microarray (r(2) = 0.91). Different markers of nonalcoholic fatty liver disease were either upregulated (e.g., Ndn and Pnpla3) or downregulated (e.g., Gnmt, Bhmt1/2, Sult1a1, Mpo, and Mat1a). Diverse pathways were altered, including hematopoiesis, coagulation cascade, complement system, and carbohydrate and lipid metabolism. The microRNAs 7a-1, 431, 146a, and 153 were upregulated, while the abundant hepatic miRNA 122 was downregulated. Constant gestational light induced extensive modification of the fetal liver transcriptome. A number of differentially expressed transcripts belong to fundamental functional pathways, potentially contributing to long-term liver disease.


Thalamic abnormalities in schizophrenia visualized through magnetic resonance image averaging.
Schizophrenia is a complex illness characterized by multiple types of symptoms involving many aspects of cognition and emotion. Most efforts to identify its underlying neural substrates have focused on a strategy that relates a single symptom to a single brain region. An alternative hypothesis, that the variety of symptoms could be explained by a lesion in midline neural circuits mediating attention and information processing, is explored. Magnetic resonance images from patients and controls were transformed with a "bounding box" to produce an "average schizophrenic brain" and an "average normal brain." After image subtraction of the two averages, the areas of difference were displayed as an effect size map. Specific regional abnormalities were observed in the thalamus and adjacent white matter. An abnormality in the thalamus and related circuitry explains the diverse symptoms of schizophrenia parsimoniously because they could all result from a defect in filtering or gating sensory input, which is one of the primary functions of the thalamus in the human brain.


Error processing in Huntington's disease.
Huntington's disease (HD) is a genetic disorder expressed by a degeneration of the basal ganglia inter alia accompanied with dopaminergic alterations. These dopaminergic alterations are related to genetic factors i.e., CAG-repeat expansion. The error (related) negativity (Ne/ERN), a cognitive event-related potential related to performance monitoring, is generated in the anterior cingulate cortex (ACC) and supposed to depend on the dopaminergic system. The Ne is reduced in Parkinson's Disease (PD). Due to a dopaminergic deficit in HD, a reduction of the Ne is also likely. Furthermore it is assumed that movement dysfunction emerges as a consequence of dysfunctional error-feedback processing. Since dopaminergic alterations are related to the CAG-repeat, a Ne reduction may furthermore also be related to the genetic disease load. We assessed the error negativity (Ne) in a speeded reaction task under consideration of the underlying genetic abnormalities. HD patients showed a specific reduction in the Ne, which suggests impaired error processing in these patients. Furthermore, the Ne was closely related to CAG-repeat expansion. The reduction of the Ne is likely to be an effect of the dopaminergic pathology. The result resembles findings in Parkinson's Disease. As such the Ne might be a measure for the integrity of striatal dopaminergic output function. The relation to the CAG-repeat expansion indicates that the Ne could serve as a gene-associated "cognitive" biomarker in HD.


EUPAN enables pan-genome studies of a large number of eukaryotic genomes.
Pan-genome analyses are routinely carried out for bacteria to interpret the within-species gene presence/absence variations (PAVs). However, pan-genome analyses are rare for eukaryotes due to the large sizes and higher complexities of their genomes. Here we proposed EUPAN, a eukaryotic pan-genome analysis toolkit, enabling automatic large-scale eukaryotic pan-genome analyses and detection of gene PAVs at a relatively low sequencing depth. In the previous studies, we demonstrated the effectiveness and high accuracy of EUPAN in the pan-genome analysis of 453 rice genomes, in which we also revealed widespread gene PAVs among individual rice genomes. Moreover, EUPAN can be directly applied to the current re-sequencing projects primarily focusing on single nucleotide polymorphisms. EUPAN is implemented in Perl, R and C ++. It is supported under Linux and preferred for a computer cluster with LSF and SLURM job scheduling system. EUPAN together with its standard operating procedure (SOP) is freely available for non-commercial use (CC BY-NC 4.0) at http://cgm.sjtu.edu.cn/eupan/index.html . email@example.com or email@example.com. Supplementary data are available at Bioinformatics online.


A comparative study of treatment outcomes between begg and edgewise orthodontic systems in class I cases.
The purpose of this study was to compare the occlusal peer assessment rating (PAR) index in Class I patients treated by means of Begg and Edgewise methods. The pre- and post-treatment study models of Class I patients, referred to two private clinics, treated with Begg method (n = 30) and standard Edgewise method (n = 30), were reviewed retrospectively using PAR index including dental displacements, buccal occlusion (anteroposterior, vertical and transverse), overjet, overbite and midline parameters. The changes in PAR indices were analyzed using paired t-test. A P < 0.05 was considered as statistically significant. There was no significant difference in sex and age distribution between the two groups. The improvement of buccal occlusion in patients treated by Begg method (1.51 ± 0.39) was significantly higher than that of patients treated by Edgewise method (0.28 ± 0.39). The duration of treatment in Begg method (17.8 ± 1.3 months) was significantly shorter than that of Edgewise method (23.7 ± 1.3 months). However, there were no significant differences between the two methods in terms of total PAR index, dental displacements, overjet, overbite and midline. In conclusion, findings of the present study indicated that Begg method might be associated with better improvement of buccal occlusion and shorter duration of treatment.


[Anesthesia for a child with congenital sensory neuropathy with anhydrosis].
We gave anesthesia twice to a 4-year-old boy with congenital sensory neuropathy with anhydrosis. At the first surgery, anesthesia was induced with midazolam and maintained with nitrous oxide, oxygen and sevoflurane 0.5-0.8% under mask breathing. Surgery was performed without any trouble but the patient vomited postoperatively for three days. Next time, anesthesia was induced and maintained with propofol under mask. The patient often moved during surgery, and therefore, we changed from propofol to oxygen and sevoflurane 1.0-1.5% anesthesia. Nitrous oxide was not used. After the surgery, no vomiting occurred.


Sequence-specific binding of poly(ADP-ribose) polymerase-1 to the human T cell leukemia virus type-I tax responsive element.
We have previously identified poly(ADP-ribose) polymerase-1 (PARP-1) as a coactivator for the human T cell leukemia virus type I (HTLV-I) transcription activator Tax. While PARP-1 is believed to contribute to DNA repair, PARP-1 has been described as a coactivator for other transcription factors. Recent evidence suggests that PARP-1 forms complexes on cellular promoters, so we investigated PARP-1 complexes on the HTLV-I Tax responsive elements (TxREs) using an end-blocked DNA binding assay. We observed sequence-specific binding of PARP-1 to the TxREs. The DNA binding domain of PARP-1 was fused to the transcriptional activation domain of VP16, and this fusion protein activated the HTLV-I promoter in a TxRE-dependent manner. Internal, sequence-specific binding of PARP-1 to DNA provides a mechanism for transcriptional regulation of the HTLV-I promoter. The mechanism of PARP-1 function in the HTLV-I system may have common mechanistic steps with other cellular promoters, including the formation of active complexes on the promoter.


Harmful delayed effects of exogenous isolation enzymes on isolated human islets: relevance to clinical transplantation.
The isolation process exposes human pancreatic islets to exogenous isolation enzymes. Exposure to these enzymes, as a result of intraductal injection in the pancreas or simple contact of islets with enzyme components, causes internalization into the islet cells of enzymes and their by-products. Human islets exposed to Liberase-HI exhibit a decreased insulin secretory ability that correlates with the time of exposure. This phenomenon is paralleled by increased expression of adhesion molecules (CD106 and CD62p) and activation of apoptotic pathways (Bax and Bcl-2) in islet cells. Increased functional impairment is also observed after islet transplantation in diabetic immunodeficient mice. Experimental exposure of islet grafts to exogenous isolation enzymes causes intense inflammation (CD11b positive cells) at the transplant site and it was associated with sickness behavior and eventually death of mouse recipients. The extent of these adverse effects likely deceives the standard qualitative protocols currently in use to assess islet quality in vitro. Reducing the secondary effects of exogenous isolation enzymes on isolated human islets may be crucial to enhance the quality of islets as tissue grafts.


Factors and co-factors influencing clinical manifestations in nsLTPs allergy: between the good and the bad.
Non-specific lipid transfer proteins (nsLTPs) are a family of plant pan-allergens that represent the primary cause of food allergies in the Mediterranean area, characterized by a wide range of clinical manifestations, ranging from the total absence of symptoms up to anaphylaxis. This wide variety of symptoms is related to the intrinsic capacity of nsLTPs to cause an allergic reaction in a specific subject, but also to the presence of co-factors exacerbating (i.e., exercise, NSAIDs, PPIs, alcohol, cannabis, prolonged fasting, menstruation, acute infections, sleep deprivation, chronic urticaria) or protecting from (i.e., co-sensitization to PR10, profilin or polcalcin) severe reactions. In this picture, recognizing some nsLTPs-related peculiarities (i.e., route, type and number of sensitizations, concentration of the allergen, cross-reactions) and eventual co-factors may help the allergist to define the risk profile of the single patient, in order to promote the appropriate management of the allergy from dietary advices up to the prescription of life-saving epinephrine autoinjector.


A Bayesian nonparametric approach for comparing clustering structures in EST libraries.
Inference for Expressed Sequence Tags (ESTs) data is considered. We focus on evaluating the redundancy of a cDNA library and, more importantly, on comparing different libraries on the basis of their clustering structure. The numerical results we achieve allow us to assess the effect of an error correction procedure for EST data and to study the compatibility of single EST libraries with respect to merged ones. The proposed method is based on a Bayesian nonparametric approach that allows to understand the clustering mechanism that generates the observed data. As specific nonparametric model we use the two parameter Poisson-Dirichlet (PD) process. The PD process represents a tractable nonparametric prior which is a natural candidate for modeling data arising from discrete distributions. It allows prediction and testing in order to analyze the clustering structure featured by the data. We show how a full Bayesian analysis can be performed and describe the corresponding computational algorithm.


Aqueous speciation studies of europium(III) phosphotungstate.
The incorporation of lanthanide ions into polyoxometalates may be a unique approach to generate new luminescent, magnetic, and catalytic functional materials. To realize these new applications of lanthanide polyoxometalates, it is imperative to understand the solution speciation chemistry and its impact on solid-state materials. In this study we find that the aqueous speciation of europium(III) and the trivacant polyoxometalate, PW9O34 9-, is a function of pH, countercation, and stoichiometry. For example, at low pH, the lacunary (PW11O39)7- predominates and the 1:1 Eu(PW11O39)4-, 2, forms. As the pH is increased, the 1:2 complex, Eu(PW11O39)2 11- species, 3, and (NH4)22[(Eu2PW10O38)4(W3O8(H2O)2(OH)4].44H2O, a Eu8 hydroxo/oxo cluster, 1, form. Countercations modulate this effect; large countercations, such as K+ and Cs+, promote the formation of species 3 and 1. Addition of Al(III) as a counterion results in low pH and formation of [Eu(H2O)3(alpha-2-P2W17O61)]2, 4, with Al(III) counterions bound to terminal W-O bonds. The four species observed in these speciation studies have been isolated, crystallized, and characterized by X-ray crystallography, solution multinuclear NMR spectroscopy, and other appropriate tech-niques. These species are 1, (NH4)22[(Eu2PW10O38)4(W3O8(H2O)2(OH)4].44H2O (P; a=20.2000(0), b=22.6951(6), c=25.3200(7) A; alpha=65.6760(10), beta=88.5240(10), gamma=86.0369(10) degrees; V=10550.0(5) A3; Z=2), 2, Al(H3O)[Eu(H2O)2PW11O34].20H2O (P, a=11.4280(23), b=11.5930(23), c=19.754(4) A; alpha=103.66(3), beta=95.29(3), gamma=102.31(3) degrees; V =2456.4(9) A3; Z=2), 3, Cs11Eu(PW11O34)2.28H2O (P; a=12.8663(14), b=19.8235(22), c=21.7060(23) A; alpha=114.57(0), beta=91.86(0), gamma=102.91(0) degrees ; V=4858.3(9) A3; Z=2), 4, Al2(H3O)8[Eu(H2O)3(alpha-2-P2W17O61)]2.29H2O (P; a=12.649(6), b=16.230(8), c=21.518(9) A; alpha=111.223(16), beta=94.182(18), gamma=107.581(17) degrees ; V=3842(3) A3; Z=1).


[Surgical treatment of cancer of the left colon. True left hemicolectomy or segmental colectomy?].
Non-metastatic cancer of the left colon is still an exclusively surgical problem in 1988. The problem is to determine which type of colectomy should be performed: either a true left hemicolectomy, a long but apparently oncologically satisfactory operation, or segmental colectomy. A recent study by A.R.C. reported the same 5-year survival for these two types of operation with essentially identical postoperative mortality and morbidity. This conclusion confirms that of many studies published on this subject.


Quantitative Volumetric Imaging and Clinical Outcome Characterization of Symptomatic Concussion in 10- to 14-Year-Old Adolescent Athletes.
Prior work suggests that younger athletes may be more vulnerable to postconcussive syndrome. We investigated measures of clinical outcome and quantitative volumetric imaging in 10- to 14-year-old adolescent athletes to better understand the impact of concussion on this younger population. Outpatient clinics. Ten- to 14-year-old symptomatic pediatric sports concussion patients and typically developing active controls. Prospective, observational multiclinic study. Demographics, magnetic resonance imaging, clinical assessments (neurocognitive function, postconcussive symptoms, mental health symptoms, quality of life). Neuropsychological performance was comparable between groups while symptoms of mental health were discriminating and comprised the top regression model describing factors related to overall health behavior impairment. Concussion patients had smaller total brain volume as well as total intracranial volume in comparison with controls even though there was no difference on measures of natural development (age, height, weight, education, gender, and handedness). Findings indicate that 10- to 14-year-old concussion patients symptomatic at 1 month more likely exhibit mental health symptoms impairing health behavior than cognitive dysfunction. There may be a vulnerability for those with smaller brain volumes at the time of the exposure. The study provides new data to support further investigation into risk factors for prolonged symptoms in this younger athlete population.


Prognostic value of preoperative serological biomarkers in patients undergoing cytoreductive surgery for ovarian cancer peritoneal metastases.
Peritoneal metastases of ovarian cancer (PMOC) are common at initial presentation. Cytoreductive surgery (CRS) of curative intent has been proven to be efficient in increasing the overall survival (OS) and the disease-free survival (DFS) of these patients. Nevertheless, CRS is associated with high postoperative morbidity, which makes patient selection a major concern. Appropriate prognostic factors that can predict patient outcomes after surgery are still lacking. Preoperative biomarkers and their ratios have been shown to be predictive of patient prognosis for various solid tumors. We aimed to study their correlation with the prognosis of patients undergoing CRS for PMOC. This retrospective study included patients with PMOC operated by CRS. Preoperative biomarkers and other clinicopathological characteristics were studied to determine their prognostic value in terms OS and DFS. 216 patients were included. Patients with preoperative hemoglobin (Hb) <11.7 g/dL had a poorer prognosis in terms of OS (p=0.0062) and DFS (p=0.0077). Additionally, increased neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR) >0.32, and platelet-to-lymphocyte ratio (PLR) >214.5 were associated with worse OS (p=0.022, p=0.0028, and p=0.0018, respectively) and worse DFS (p=0.028, p=0.003, and p=0.019, respectively). Multivariate analysis showed that the variables mentioned above were independent predictive factors for OS and DFS. Preoperative Hb level, NLR, MLR, and PLR are prognostic factors for OS and DFS in PMOC patients operated by curative CRS.


[Metastatic Lung Tumor Diagnosed as Primary Lung Cancer due to its Accompanying Lesion Mimicking Atypical Adenomatous Hyperplasia by Intraoperative Needle Biopsy Findings;Report of a Case].
We reported a case of metastatic lung tumor, which was suspected as being a primary lung cancer because of its accompanying lesion mimicking atypical adenomatous hyperplasia(AAH) based on intraoperative needle biopsy findings. AAH is a preinvasive lesion or marginal lesion of primary lung cancer that is not accompanied by metastatic tumor. However, it needs to be distinguished pathologically from secondary changes of inflammation or fibrosis. In our case, the needle biopsy revealed AAH-like pathological findings, which indicates a primary lung cancer, and the standard lobectomy with lymph node dissection was performed, however, the final diagnosis turned out to be metastatic tumor. The rapidly enlarging tumor led to surrounding obstructive pneumonitis, which may have caused pathological changes mimicking AAH findings. In the case of obstructive pneumonitis, we must be careful to diagnose AAH, in addition to decisions about the surgical procedure especially when based on frozen section diagnosis.


Behind a mask: tricks, pitfalls, and prejudices for noninvasive ventilation.
It is difficult to exactly date the beginning of mechanical ventilation, but there are no doubts that noninvasive ventilation (NIV) was the first method of ventilatory support in clinical practice. The technique had a sudden increase in popularity, so that it is now considered, according to criteria of evidence-based medicine, the first-line treatment for an episode of acute respiratory failure in 4 pathologies (the Fabulous Four): COPD exacerbation, cardiogenic pulmonary edema, pulmonary infiltrates in immunocompromised patients, and in the weaning of extubated COPD patients. The so-called emerging applications are those for which the evidence has not achieved level A, mainly because the number or sample size of the published studies does not allow conclusive meta-analysis. These emerging applications are the post-surgical period, palliation of dyspnea, asthma attack, obesity hypoventilation syndrome, and to prevent extubation failure. Potentially "risky business" uses include for respiratory failure from pandemic diseases and ARDS, where probably the "secret" for success is early use. Healthcare is rich in evidence-based innovations, yet even when such innovations are implemented successfully in one location, they often disseminate slowly, if at all, so their clinical use remains limited and heterogeneous. The low rate of NIV use in some hospitals relates to lack of knowledge about or experience with NIV, insufficient confidence in the technique, lack of NIV equipment, and inadequate funding. But NIV use has been increasing around the world, thanks partly to improved technologies. The skill and confidence of clinicians in NIV have improved with time and experience, but NIV is and should remain a team effort, rather than the property of a single local "champion," because, overall, NIV is beautiful!


Sleep disturbances in Chinese pregnant women.
In a prospective study of 247 pregnant Chinese women, the prevalence of sleep disturbances across pregnancy has been assessed using a set of validated questionnaires including the Sleep and Health Questionnaire (SHQ) and the Epworth Sleepiness Scale (ESS). The frequency of self-reported snoring increased from 29.7% in the first trimester to 40.5% and 46.2% in the second and third trimesters, respectively, with an increase in the prevalence of moderate or severe snoring from 1% in the first trimester to 7.2% in the third trimester (P < 0.01). There was a higher frequency of moderate to severe snoring intensity among subjects with BMI >or=25 compared with those with BMI <25 kg/m(2) in the third trimester (20.8%vs 5.3%, P < 0.01). Subjective sleepiness, as determined by the ESS, increased significantly from 8.6 to 9.4 and 9.6 in the first, second and third trimesters, respectively.


Glowing selenates: novel alkaline earth nanoparticles.
Up to now, no selenate nanoparticles have been described even though much research has been done on respective oxidic compounds such as sulfates and phosphates. For the first time, alkaline earth selenates of the composition MSeO4 (M = Ca, Sr, Ba) were synthesized as nanoparticles or nanorods as described in this publication. For this purpose, a micro emulsion method was applied using CTAB as a surfactant. Using X-ray diffraction measurements (XRD) phase purity of the materials could be proven. Furthermore, the nanoparticles were analyzed by raster electron microscopy (REM) and dynamic light scattering (DLS) measurements. Finally, the products were doped with small amounts of Eu3+ to obtain luminescent materials. Successful doping was demonstrated by luminescence investigations in the region of 18 000 to 14 000 cm-1 (550-715 nm). Incorporation of Eu3+ led to strong red-emitting nanoparticles. Low temperature measurements at 10 K allowed conclusions about the site symmetry of Eu3+ ions located on the alkaline earth sites.


Design of pH-Responsive Polymer Monolith Based on Cyclodextrin Vesicle for Capture and Release of Myoglobin.
β-Cyclodextrin vesicles (CDVs) were first introduced into the polymer monolith to prepare a pH-responsive adsorption material and used for capture and release of a cardiac biomarker, myoglobin (Myo). SH-CDV was decorated with adamantane-modified SH-octapeptide to enhance the encapsulation and release rates of Myo. Afterward, SH-CDV was introduced into the polymer monolith via click reaction to produce a pH-responsive monolith. Combining with the mass spectrometry detection, the CDV-based pH-responsive monolith was used for the enrichment of Myo glycopeptides from the mixture of glycopeptides and nonglycoprotein (bovine serum albumin) tryptsin digests reach up to 1:10 000. A limit of detection of 0.1 fmol was obtained for Myo glycopeptides in the blood sample, indicating the high sensitivity of the method. The prepared CDV-based hybrid monolith demonstrated itself to be a promising material for capture of glycoproteins in complex samples, which provides an efficient strategy for the identification and discovery of biomarkers of acute myocardial infarction.


Are genes encoding proteoglycans really associated with the risk of anterior cruciate ligament rupture?
Proteoglycans are considered integral structural components of tendon and ligament and have been implicated in the resistance of compressive forces, collagen fibrillogenesis, matrix remodelling and cell signalling. Several sequence variants within genes encoding proteoglycans were recently implicated in modulating anterior cruciate ligament ruptures (ACLR). This study aimed to test the previously implicated variants in proteoglycan and vascular epithelial growth factor encoding genes with risk of ACLR in a population from Poland. A case control genetic association study was conducted using DNA samples from 143 healthy participants without a history of ACL injuries (99 male and 44 females) (CON group) and 229 surgically diagnosed ACLR participants (158 males and 71 females). All samples were genotyped for the ACAN: rs1516797, BGN: rs1042103, rs1126499, DCN: rs516115 and VEGFA: rs699947 variants. Main findings included the (i) ACAN rs1516797 G/T genotype which was underrepresented in the CON group (CON: 36%, n=52, ACLR: 49%, n=112, p=0.017, OR=1.68, 95% CI 1.09 to 2.57) when all participants were investigated and (ii) the BGN rs1042103 A allele was significantly under-represented in the male CON group compared to the male ACLR group (CON: 39%, n=78, ACLR: 49%, n=156, p=0.029, OR=1.5, 95% CI 1.05 to 2.15). Furthermore, BGN inferred haplotypes were highlighted with altered ACLR susceptibility. Although the study implicated the ACAN and BGN genes (combination of genotype, allele and haplotype) in modulating ACLR susceptibility, several differences were noted with previous published findings.


Dual Signal Amplification by Urease Catalysis and Silver Nanoparticles for Ultrasensitive Colorimetric Detection of Nucleic Acids.
Signal amplification techniques are highly desirable for the analysis of low-level targets that are closely related with diseases and the monitoring of important biological processes. However, it is still challenging to achieve this goal in a facile and economical way. Herein, we developed a novel dual signal amplification strategy by combining urease catalysis with the release of Ag+ from silver nanoparticles (AgNPs). This strategy was used for quantifying a DNA sequence (HIV-1) related with human immunodeficiency virus (HIV). DNA target HIV-1 hybridizes with the capture DNA probe on magnetic beads and the reporter DNA probe on AgNPs, forming a sandwich complex. The captured AgNPs are then transformed into numerous Ag+ ions that inactivate numerous ureases. Without catalytic production of ammonia from urea, the substrate solution shows a low pH 5.8 that will increase otherwise. The pH change is monitored by a pH indicator (phenol red), which allows for colorimetric detection. The proposed approach is sensitive, easy to use, economic, and universal, exhibiting a low detection limit of 9.7 fM (i.e., 1.94 attomoles) and a dynamic linear range of 4 orders for HIV-1 sequence detection.


The neural basis of humour comprehension and humour appreciation: The roles of the temporoparietal junction and superior frontal gyrus.
Psychological well-being and social acumen benefit from the recognition of humourous intent and its enjoyment. The enjoyment of humour requires recognition, but humour recognition is not necessarily accompanied by humour enjoyment. Humour recognition is crucial during social interactions, while the associated enjoyment is less critical. Few neuroimaging studies have explicitly differentiated between the neural foundations of humour comprehension and humour appreciation. Among such studies, design limitations have obscured the specification of neural correlates to humour comprehension or appreciation. We implemented a trichotomous response option to address these design limitations. Twenty-four participants rated 120 comics (90 unaltered with humourous intent and 30 caption-altered without humourous intent) as either funny jokes (FJ), not funny jokes but intended to be funny (NFJ), or not intended to be funny or non-jokes (NJ). We defined humour comprehension by NFJ minus NJ and humour appreciation by FJ minus NFJ. We measured localized blood oxygen level dependent (BOLD) neural responses with a 3T MRI scanner. We tested for BOLD responses in humour comprehension brain regions of interest (ROIs), humour appreciation ROIs, and across the whole-brain. We found significant NFJ-NJ BOLD responses in our humour comprehension ROIs and significant FJ-NFJ BOLD responses in select humour appreciation ROIs. One key finding is that comprehension accuracy levels correlated with humour-comprehension responses in the left temporo-parietal junction (TPJ). This finding represents a novel and precise neural linkage to humour comprehension. A second key finding is that the superior frontal gyrus (SFG) was uniquely associated with humour-appreciation. The SFG response suggests that complex cognitive processing underlies humour appreciation and that current models of humour appreciation be revised. Finally, our research design provides an operational distinction between humour comprehension and appreciation and a sensitive measure of individual differences in humour comprehension accuracy.


Polo-like kinase 1 expression is suppressed by CCAAT/enhancer-binding protein α to mediate colon carcinoma cell differentiation and apoptosis.
Human polo-like kinase 1 (PLK1), a highly conserved serine/threonine kinase is a key player in several essential cell-cycle events. PLK1 is considered an oncogene and its overexpression often correlates with poor prognosis of cancers, including colorectal cancer (CRC). However, regulation of PLK1 expression in colorectal cells was never studied earlier and it is currently unknown if PLK1 regulates differentiation and apoptosis of CRC. PLK1 expression was analyzed by real-time PCR and western blotting. Transcriptional regulation was studied by reporter assay, gene knock-down, EMSA and ChIP. PLK1 expression was down-regulated during butyrate-induced differentiation of HT-29 and other CRC cells. Also, PLK1 down-regulation mediated the role of butyrate in CRC differentiation and apoptosis. We report here a novel transcriptional regulation of PLK1 by butyrate. Transcription factors CCAAT/enhancer-binding protein α (C/EBPα) and Oct-1 share an overlapping binding site over the PLK1 promoter. Elevated levels of C/EBPα by butyrate treatment of CRC cells competed out the activator protein Oct-1 from binding to the PLK1 promoter and sequestered it. Binding of C/EBPα was associated with increased deacetylation near the transcription start site (TSS) of the PLK1 promoter, which abrogated transcription through reduced recruitment of RNA polymerase II. We also found a synergistic role between the synthetic PLK1-inhibitor SBE13 and butyrate on the apoptosis of CRC cells. This study offered a novel p53-independent regulation of PLK1 during CRC differentiation and apoptosis. Down-regulation of PLK1 is one of the mechanisms underlying the anti-cancer role of dietary fibre-derived butyrate in CRC.


A functional tool demonstrating the physical function decline independentof age in patients with predialysis chronic kidney disease.
Physical function decline in chronic kidney disease (CKD) patients has been a popular area of investigation in the last decade. It has been shown that lower levels of physical function in CKD results in poor outcomes. Nevertheless, nephrology practice does not include routine assessment of physical function. The aim of the present study is to elucidate which physical function assessment tool is better in CKD. A total of 148 predialysis CKD patients and 40 healthy controls were included in this cross-sectional single-blind study. CKD patients were further divided into two groups as stage 3 and stage 4/5. A hand dynamometer, the Short Physical Performance Battery (SPPB), and the Timed Up and Go Test (TUGT) were applied to all study participants. All physical function tests were significantly different between study and control groups. In multivariate analysis the SPPB (P < 0.001) emerged as an independent variable in CKD group. The SPPB is a promising, easily applicable, inexpensive, and sensitive tool that can indicate functional decline independent of age in predialysis CKD patients and can be used in clinical practice to monitor these patients.


Can testing immunize memories against interference?
Testing typically enhances subsequent recall of tested material. In contrast, it has been proposed that consolidated memories can be destabilized when reactivated and then need to be reconsolidated in order to persist. Learning new material immediately after reactivation may disrupt reconsolidation. We investigated whether the well-known benefits of testing are counterbalanced by a tendency for retrieval to make memory more susceptible to interference. Participants learned 20 English-Swahili word pairs (List 1) on Day 1. On Day 2 one group of participants took a reminder test of List 1 immediately before learning 20 English-Finnish word pairs sharing the same cues (List 2). A second group learned List 2 without taking the reminder test of List 1, a third took the reminder test alone, and a fourth group did nothing on Day 2. On Day 3 all participants took a final test. The reminder test, far from impairing List 1 memory, enhanced it, revealing a testing effect. Furthermore, List 2 learning disrupted List 1 memory when there was no reminder test, but reminder testing immunized the memory against interference.


The Ethical and Legal Dilemma in Terminating the Physician-Patient Relationship.
A physician-patient relationship is essential for the well-being of the patient, for without a strong and trusting relationship between both individuals, the patient may not receive the best care that they deserve. There are many legal policies and ethical principles a physician must follow when caring for a patient. It is both the legal and moral duty of the physician to act in the best interests of their patients, while making sure to respect them regardless of background and personal behaviours. The relationship is secured with both trust and respect, for without trust, the patient may hold back from stating their conditions which will result in the physician not providing them with all the care they require. Sometimes, lack of some of these key characteristics of the physician-patient relationship and other circumstances, may cause either the patient or the physician to terminate the relationship. Termination of a relationship creates a difficult situation for the patient, and therefore there are only specific situations where a physician may have permission to follow through and terminate their relationship. Both the law and ethical principles play a role in the decisions made by the physician in regards to their relationship with the patient, but regardless, the physician has the obligation to make sure their patient is receiving care by one means or another.


Extracellular Hsp90 and protection of neuronal cells through Nrf2.
Heat shock protein 90 (Hsp90), although one of the most essential intracellular chaperones, can also play key roles in the extracellular milieu. Here, we review the properties of extracellular Hsp90 in cellular homeostasis in the heat shock response (HSR), focusing on cells of the central nervous system. Hsp90 can be secreted by microglia as well as other cell types by non-canonical pathways of secretion. The chaperone may then influence the behavior of distant cells and can for instance protect neuronal cells from the oxidative burst accompanying phagocytosis by microglia of beta-amyloid fibrils. A mechanism involving activation of the transcription factor Nrf2, and induction of the antioxidant response is reported. We review the potential role of extracellular Hsp90, Nrf2 and transcellular chaperone signaling in the non-cell-intrinsic HSR.


Genome-wide association for grain yield under rainfed conditions in historical wheat cultivars from Pakistan.
Genome-wide association studies (GWAS) were undertaken to identify SNP markers associated with yield and yield-related traits in 123 Pakistani historical wheat cultivars evaluated during 2011-2014 seasons under rainfed field conditions. The population was genotyped by using high-density Illumina iSelect 90K single nucleotide polymorphism (SNP) assay, and finally 14,960 high quality SNPs were used in GWAS. Population structure examined using 1000 unlinked markers identified seven subpopulations (K = 7) that were representative of different breeding programs in Pakistan, in addition to local landraces. Forty four stable marker-trait associations (MTAs) with -log p > 4 were identified for nine yield-related traits. Nine multi-trait MTAs were found on chromosomes 1AL, 1BS, 2AL, 2BS, 2BL, 4BL, 5BL, 6AL, and 6BL, and those on 5BL and 6AL were stable across two seasons. Gene annotation and syntey identified that 14 trait-associated SNPs were linked to genes having significant importance in plant development. Favorable alleles for days to heading (DH), plant height (PH), thousand grain weight (TGW), and grain yield (GY) showed minor additive effects and their frequencies were slightly higher in cultivars released after 2000. However, no selection pressure on any favorable allele was identified. These genomic regions identified have historically contributed to achieve yield gains from 2.63 million tons in 1947 to 25.7 million tons in 2015. Future breeding strategies can be devised to initiate marker assisted breeding to accumulate these favorable alleles of SNPs associated with yield-related traits to increase grain yield. Additionally, in silico identification of 454-contigs corresponding to MTAs will facilitate fine mapping and subsequent cloning of candidate genes and functional marker development.