Plasmon induced magneto-optical enhancement in metallic Ag/FeCo core/shell nanoparticles synthesized by colloidal chemistry.
The combination of magnetic and plasmonic materials and their nanostructurization have revealed a prominent pathway to develop novel photonic materials for the active control of the light polarization using a magnetic field. Until now, physical growth methods have been the only exploitable approach to prepare these types of nanostructures. Here, we demonstrate the chemical synthesis of magneto-plasmonic core/shell nanocrystals with enhanced magnetic control of optical properties comparable to the best results reported for nanostructure growth by physical methods. Ag/FeCo core/shell nanocrystals were synthesized using a combination of hot injection and polyol approaches, demonstrating that the well-defined structures of both components, their interface and the optimized morphology, where the plasmonic and magnetic components are placed in the core and the shell regions, are responsible for the observed large enhancement of magnetic control of light polarization. Therefore, there is a possibility to develop tunable magneto-optical materials from hybrid magneto-plasmonic structures synthesized by chemical methods.


Pathological characteristics of cervical adenocarcinoma in a multi-center US-based study.
Difficulties in detecting cervical adenocarcinoma early are well known. We report a detailed pathology review of cervical adenocarcinoma subtypes, comparing growth patterns and appearance of non-neoplastic epithelium to inform possible clues for disease progression and early detection. This analysis includes 154 women aged 18-69 years and diagnosed with incident in situ or invasive adenocarcinoma (AC), adenosquamous (AS), or other rare cervical glandular tumors from 1992-1996 in six U.S. medical centers. A pathology review panel evaluated histological features from original diagnostic slides. Higher tumor grade (P < 0.001) and vascular invasion (P = 0.002) were more common in AS compared to AC. Adenocarcinoma in situ (AIS) was also more common among AC than AS (P = 0.002). Among AC with cervical intraepithelial carcinoma (CIN), AIS and cribriform patterns were more common than AC without CIN (P = 0.01). Further, non-endometrioid AC had higher tumor grade (P = 0.01) and stromal responses (P = 0.02) than endometrioid AC. Finally, although microglandular hyperplasia is historically thought to be related to oral contraceptive (OC) use, our data do not support this notion. AS appears to be either diagnosed later or histologically more aggressive than AC, and among AC subtypes, there are distinct histologic characteristics. Further research is needed to identify precursor lesions for early detection of AC and particularly for AS where AIS may not be a common precursor.


Effects of diet acidity and protein level or source of calcium on the performance, gastrointestinal content measurements, bone measurements, and carcass composition of gilt and barrow weanling pigs.
A total of 228 crossbred weanling pigs (average age of 25 d and BW of 6.44 kg) were used in two trials to evaluate the responses to sex, diet acidity, protein level, and source of calcium on the performance, gastrointestinal digesta measurements, bone measurements, and carcass composition. Diet acidity was manipulated by varying the sources of supplemental phosphorus in the diets. Trial 1 (5 wk) was conducted as a 2 x 3 x 2 factorial to evaluate sex (gilts and barrows), diet acidity (pH 5.9 and .90% P, pH 6.1 and .63% P, and pH 6.9 and .63% P), and level of protein (16 and 22% CP). In Trial 2 (6 wk), diet acidity (pH 5.5, 5.9, and 6.8, all with .7% P) and Ca sources (CaCO3 and CaSO4) were used with gilts and barrows. The sex x diet acidity interactions were significant for ADG in both trials. Barrows seemed to respond to both the more acidic diets and the buffered phosphate diets even though the pH was less acidic than that of the unbuffered diets. Gilts responded only to the more acidic diets. In Trial 1, gilts ate more and grew faster (P < .05) than barrows, but no sex effects on performance were observed in Trial 2. Pigs fed 22% CP diets grew faster (P < .001) and more efficiently (P < .001) than did pigs fed 16% CP diets, but protein level x diet acidity and protein level x sex interactions were not significant. Stomach digesta DM, pH, and titration value were not consistently influenced by sex and diet acidity in Trials 1 and 2, by protein level in Trial 1, and by calcium source in Trial 2. Only the sex x diet acidity interaction for stomach DM tended to be significant in both trials; gilts fed the less acidic diets had the lowest DM, whereas barrows fed the more acidic diets had the lowest DM values. Although not significant in every case in both trials, bone (average of metacarpal and metatarsal) volume was lower and specific gravity and shear stress values were higher for gilts than for barrows. Pigs fed 16% CP diets had higher specific gravity (P < .05) and stress (P < .06) values than pigs fed 22% CP diets. A protein level x diet acidity interaction (P < .03) for stress suggested that pigs fed 22% CP diets were unaffected by diet acidity, whereas pigs fed 16% CP had the highest stress values when fed the more acidic diet and the lower P level.(ABSTRACT TRUNCATED AT 250 WORDS)


Diversity of the nitrite reductase gene nirS in the sediment of a free-water surface constructed wetland.
The diversity of the nitrite reductase gene nirS was studied in the bulk sediment of a free-water surface constructed wetland (FWS-CW) located next to the Empuriabrava wastewater treatment plant (WWTP), in Castelló d'Empúries (Girona, NE Spain). The study period extended from the inception of the treatment wetland, in June 1998, until March 1999 and comprised periods of relatively high nitrate and ammonium concentrations at the influent and low nitrate-removal efficiencies. To evaluate nirS diversity, partial gene sequences were obtained by cloning of the respective PCR products. Rarefaction curves based on DOTUR analyses of the deduced amino-acid sequences predicted a greater diversity of nirS genes in samples containing higher ammonium concentrations. Estimated Shannon-Weaver indices of the four cloned samples showed a positive relationship with the N-NH4 +/N-NO3 - ratios measured at the FWS-CW inlet. Identities between the deduced amino-acid sequences and those previously deposited in public databases ranged from 72 to 97%. Phylogenetic analysis based on these deduced sequences grouped 165 nirS clones in seven main clusters according to high similarity indices. Up to 60% of the clones clustered together in a highly homogeneous group with little homologies to any sequence retrieved from cultured representatives. Moreover, prevailing environmental conditions appeared to select for particular denitrifying populations, e.g., with respect to ammonium load and nitrogen removal efficiencies. This observation is of particular interest for the management of treatment wetlands, in which only slight variations in the theoretical denitrification potential of the system can occur.


Adverse events following first and second dose COVID-19 vaccination in England, October 2020 to September 2021: a national vaccine surveillance platform self-controlled case series study.
BackgroundPost-authorisation vaccine safety surveillance is well established for reporting common adverse events of interest (AEIs) following influenza vaccines, but not for COVID-19 vaccines.AimTo estimate the incidence of AEIs presenting to primary care following COVID-19 vaccination in England, and report safety profile differences between vaccine brands.MethodsWe used a self-controlled case series design to estimate relative incidence (RI) of AEIs reported to the national sentinel network, the Oxford-Royal College of General Practitioners Clinical Informatics Digital Hub. We compared AEIs (overall and by clinical category) 7 days pre- and post-vaccination to background levels between 1 October 2020 and 12 September 2021.ResultsWithin 7,952,861 records, 781,200 individuals (9.82%) presented to general practice with 1,482,273 AEIs, 4.85% within 7 days post-vaccination. Overall, medically attended AEIs decreased post-vaccination against background levels. There was a 3-7% decrease in incidence within 7 days after both doses of Comirnaty (RI: 0.93; 95% CI: 0.91-0.94 and RI: 0.96; 95% CI: 0.94-0.98, respectively) and Vaxzevria (RI: 0.97; 95% CI: 0.95-0.98). A 20% increase was observed after one dose of Spikevax (RI: 1.20; 95% CI: 1.00-1.44). Fewer AEIs were reported as age increased. Types of AEIs, e.g. increased neurological and psychiatric conditions, varied between brands following two doses of Comirnaty (RI: 1.41; 95% CI: 1.28-1.56) and Vaxzevria (RI: 1.07; 95% CI: 0.97-1.78).ConclusionCOVID-19 vaccines are associated with a small decrease in medically attended AEI incidence. Sentinel networks could routinely report common AEI rates, contributing to reporting vaccine safety.


Efficacy of Endoscopic Over 3-branched Partial Stent-in-Stent Drainage Using Self-expandable Metallic Stents in Patients With Unresectable Hilar Biliary Carcinoma.
The treatment of biliary stricture is crucially important for continuing stable chemotherapy for unresectable biliary carcinoma; however, there is no consensus regarding the use of hilar biliary drainage. In this study, we examined the efficacy of endoscopic over 3-branched biliary drainage using self-expandable metallic stents (SEMSs) in patients with unresectable malignant hilar biliary stricture (HBS). A total of 77 patients with unresectable HBS treated with a SEMS and chemotherapy were retrospectively reviewed. There were 59 patients with cholangiocarcinoma and 18 patients with gallbladder carcinoma. The patients were divided into 2 groups (4- or 3-branched group and 2- or 1-branched group) and compared with respect to the duration of stent patency and overall survival. A comparison of the patients' baseline characteristics showed no significant differences between the 4- or 3-branched group and the 2- or 1-branched group. Neither the duration of patency nor survival time exhibited significant differences between the 2 groups, although, among the patients achieving disease control , the duration of patency period and survival time of the 4- or 3-branched group were significantly higher than those observed in the 2- or 1-branched group (P=0.0231 and 0.0466). The use of endoscopic over 3-branched biliary drainage with a SEMS may improve the duration of patency in patients with HBS.


Risk factors of Internet addiction and the health effect of internet addiction on adolescents: a systematic review of longitudinal and prospective studies.
Internet gaming addiction was included in the latest version of the DSM-V as a possible disorder recently, while debate is still on-going as to whether the condition called "Internet Addiction" (IA) could be fully recognised as an established disorder. The major contention is how well IA could fulfil the validation criteria as a psychiatric disorder as in other well-established behavioural addictions. In addition to various proposed validation criteria, evidence of risk and protective factors as well as development of outcomes from longitudinal and prospective studies are suggested as important. A systematic review of available longitudinal and prospective studies was conducted to gather epidemiological evidence on risk and protective factors of IA and the health effect of IA on adolescents. Nine articles were identified after an extensive search of the literature in accordance to the PRISMA guidelines. Of these, eight provided data on risk or protective factors of IA and one focused solely on the effects of IA on mental health. Information was extracted and analysed systematically from each study and tabulated. Many exposure variables were studied and could be broadly classified into three main categories: psychopathologies of the participants, family and parenting factors, and others such as Internet usage, motivation, and academic performance. Some were found to be potential risk or protective factors of IA. It was also found that exposure to IA had a detrimental effect on the mental health of young people. These results were discussed in light of their implications to the fulfilment of the validation criteria.


XAS investigation of the structure and function of Ni in acireductone dioxygenase.
Acireductone dioxygenases (ARDs) are enzymes involved in the methionine recycle pathway, which regulates aspects of the cell cycle. Klebsiella pneumoniae produces two enzymes that share a common polypeptide sequence and differ only in the metal ion present. Reaction of acireductone (1,2-dihydroxy-3-keto-5-methylthiopentene) with Fe-ARD and dioxygen produces formate and 2-keto-4-methylthiobutanoic acid, the alpha-ketoacid precursor of methionine. Ni-ARD reacts with acireductone and dioxygen to produce methylthiopropionate, CO, and formate and does not lie on the methionine recycle pathway. An X-ray absorption spectroscopy (XAS) study of the structure of the catalytic Ni center in resting Ni-ARD enzyme and the enzyme-substrate complex is reported. This study establishes the structure of the Ni site in resting Ni-ARD as containing a six coordinate Ni site composed of O/N-donor ligands including 3-4 histidine residues, demonstrates that the substrate binds to the Ni center in a bidentate fashion by displacing two ligands, at least one of which is a histidine ligand, and provides insight into the mechanism of catalysis employed by a Ni-containing dioxygenase. Efficiently relaxed and hyperfine-shifted resonances are observed in the (1)H nuclear magnetic resonance spectrum of Ni-ARD that can be attributed to the His imidazoles ligating the paramagnetic Ni ion and are consistent with the XAS results regarding His ligation. These resonances show significant perturbation in the presence of substrate, confirming that the metal ion interacts directly with the substrate.


In vivo interactions of RNA polymerase II with genes of Drosophila melanogaster.
We describe a method for examining the in vivo distribution of a protein on specific eucaryotic DNA sequences. In this method, proteins are cross-linked to DNA in intact cells, and the protein-DNA adducts are isolated by immunoprecipitation with antiserum against the protein. Characterization of the DNA cross-linked to the precipitated protein identifies the sequences with which the protein is associated in vivo. Here, we applied these methods to detect RNA polymerase II-DNA interactions in heat-shocked and untreated Drosophila melanogaster Schneider line 2 cells. The level of RNA polymerase II associated with several heat shock genes increased dramatically in response to heat shock, whereas the level associated with the copia genes decreased, indicating that both induction of heat shock gene expression and repression of the copia gene expression by heat shock occur at the transcriptional level. Low levels of RNA polymerase II were present on DNA outside of the transcription units, and for at least two genes, hsp83 and hsp26, RNA polymerase II initiated binding near the transcription start site. Moreover, for hsp70, the density of RNA polymerase II on sequences downstream of the polyadenylate addition site was much lower than that observed on the gene internal sequences. Examination of the amount of specific restriction fragments cross-linked to RNA polymerase II provides a means of detecting RNA polymerase II on individual members of multigene families. This analysis shows that RNA polymerase II is associated with only one of the two cytoplasmic actin genes.


Application of the 'gate effect' of a molecularly imprinted polymer grafted on an electrode for the real-time sensing of heparin in blood.
Heparin is the most important anticoagulant drug used during surgeries and extracorporeal therapies. Although the blood levels of heparin should be monitored continuously during the procedure to ensure the safety of the patient, there is currently no technique for measuring heparin in real time. This study describes the use of a molecularly imprinted polymer (MIP) as a recognition element in the development of a heparin sensor for real-time monitoring. An indium tin oxide (ITO) electrode grafted with a heparin-specific MIP was used as a working electrode to perform cyclic voltammetry of ferrocyanide. The anodic current was found to be dependent on heparin concentration, probably due to the "gate effect", which is a change in the accessibility of the MIP-modified electrode to ferrocyanide, triggered by specific interaction between MIP and heparin. The kinetics of heparin interaction with the MIP-grafted electrode was evaluated using potentiostatic chronoamperometry of ferrocyanide in an electrochemical flow cell. The response time to stepwise changes in heparin concentration between 0 and 0.04 units per mL was estimated at 20 s, which is remarkably shorter than that achieved using conventional methods for monitoring heparin. The MIP-grafted electrode demonstrated exceptional sensitivity and could detect heparin in whole blood samples (0-6 units per mL) diluted 100-fold with physiological saline containing ferrocyanide. Therefore, the MIP-grafted electrode is suitable for real-time monitoring of heparin in blood. Another advantage is that a very small volume of blood is needed, which is very important, especially when regular measurements are required.


The genetic depletion or the triptolide inhibition of TFIIH in p53-deficient cells induces a JNK-dependent cell death in Drosophila.
Transcription factor IIH (TFIIH) participates in transcription, nucleotide excision repair and the control of the cell cycle. In the present study, we demonstrate that the Dmp52 subunit of TFIIH in Drosophila physically interacts with the fly p53 homologue, Dp53. The depletion of Dmp52 in the wing disc generates chromosome fragility, increases apoptosis and produces wings with a reduced number of cells; cellular proliferation, however, is not affected. Interestingly, instead of suppressing the apoptotic phenotype, the depletion of Dp53 in Dmp52-depleted wing disc cells increases apoptosis and the number of cells that suffer from chromosome fragility. The apoptosis induced by the depletion of Dmp52 alone is partially dependent on the JNK pathway. In contrast, the enhanced apoptosis caused by the simultaneous depletion of Dp53 and Dmp52 is absolutely JNK-dependent. In this study, we also show that the anti-proliferative drug triptolide, which inhibits the ATPase activity of the XPB subunit of TFIIH, phenocopies the JNK-dependent massive apoptotic phenotype of Dp53-depleted wing disc cells; this observation suggests that the mechanism by which triptolide induces apoptosis in p53-deficient cancer cells involves the activation of the JNK death pathway.


First Report of Bacterial Soft Rot of Potato Caused by Pectobacterium carotovorum subsp. carotovorum in Guangdong Province of China.
Potato (Solanum tuberosum L.) is a major crop in China, with 80.0 million tons being produced in 2010 on 3.3 million ha. Pectobacterium carotovorum subsp. carotovorum Jones 1901; Hauben et al. 1999 causes soft rot worldwide on a wide range of hosts including potato, carrot, and cabbage. During spring 2010, a soft rot with a foul smell was noted in stored potato tubers of different cultivars in the Guangdong Province. Symptoms on tubers appeared as tan, water-soaked areas with watery ooze. The rotted tissues were white to cream colored. Stems of infected plants with typical inky black symptoms could also be found in the fields prior to harvest. Three different potato fields were surveyed, and 13% of the plants had the symptoms. Twenty-seven samples (three symptomatic tubers per sample) were collected. Bacteria were successfully isolated from all diseased tissues on nutrient agar media supplemented with 5% sucrose and incubated at 26 ± 1°C for 36 h. After purification on tripticase soy agar media, four typical strains (7-3-1, 7-3-2, 8-3-1, and 8-3-2) were identified using the following deterministic tests: gram-negative rods, oxidase negative, facultatively anaerobic, able to degrade pectate, sensitive to erythromycin, negative for phosphatase, unable to produce acid from α-methyl-glucoside, and produced acid from trehalose. Biolog analysis (Ver 4.20.05, Hayward, CA) identified the strains as P. carotovorum subsp. carotovorum (SIM 0.808, 0.774, 0.782, and 0.786, respectively). The identity of strains 7-3-1 (GenBank Accession No. JX258132), 7-3-2 (JX258133), and 8-3-1 (JX196705) was confirmed by 16S rRNA gene sequencing (4), since they had 99% sequence identity with other P. carotovorum subsp. carotovorum strains (GenBank Accession Nos. JF926744 and JF926758) using BLASTn. Further genetic analysis of strain 8-3-1 was performed targeting informative housekeeping genes, i.e., acnA (GenBank Accession No. JX196704), gabA (JX196706), icdA (JX196707), mdh (JX196708), mtlD (JX196709), pgi (JX196710), and proA (JX196711) (2). These sequences from strain 8-3-1 were 99 to 100%, homologous to sequences of multiple strains of P. carotovorum subsp. carotovorum. Therefore, strain 8-3-1 grouped with P. carotovorum subsp. carotovorum on the phylogenetic trees (neighbor-joining method, 1,000 bootstrap values) of seven concatenated housekeeping genes when compared with 60 other strains, including Pectobacterium spp. and Dickeya spp. (3). Pathogenicity of four strains (7-3-1, 7-3-2, 8-3-1, and 8-3-2) was evaluated by depositing a bacterial suspension (106 CFU/ml) on the potato slices of cultivar 'Favorita' and incubating at 30 ± 1°C. Slices inoculated with just water served as non-inoculated checks. The strains caused soft rot within 72 h and the checks had no rot. Bacteria were reisolated from the slices and were shown to be identical to the original strains based on morphological, cultural, and biochemical tests. Although this pathogen has already been reported in northern China (1), to our knowledge, this is the first report of P. carotovorum subsp. carotovorum causing bacterial soft rot of potato in Guangdong Province of China. References: (1) Y. X. Fei et al. J. Hexi Univ. 26:51, 2010.(2) B. Ma et al. Phytobacteriology 97:1150, 2007. (3) S. Nabhan et al. Plant Pathol. 61:498, 2012. (4) W. G. Weisbury et al. J. Bacteriol. 173:697, 1991.


Myocardial potency of Bio-tea against Isoproterenol induced myocardial damage in rats.
Kombucha (Bio-tea) is a beverage produced by the fermentation of sugared black tea using a symbiotic association of bacteria and yeasts. Traditional claims about Kombucha report beneficial effects such as antibiotic properties, gastric regulation, relief from joint rheumatism and positive influence on the cholesterol level, arteriosclerosis, diabetes, and aging problems. The present investigation was carried out to understand the preventive effect of Kombucha on heart weight, blood glucose, total protein, lipid profile and cardiac markers in rats with myocardial damage induced using Isoproterenol. As Bio-tea is produced by fermenting tea, the parameters were compared in rats pre-treated with normal black tea and Bio-tea for 30 days followed by subcutaneous injection of Isoproterenol (85 mg/kg body weight). Normal rats as well as Isoproterenol induced myocardial infarcted rats were also used, which served as controls. Isoproterenol induced myocardial infarcted control rats showed a significant increase in heart weight, blood glucose and cardiac markers and a decrease in plasma protein. Increased levels of cholesterol, triglycerides, low density lipids (LDL) and very low density lipids (VLDL) were also observed, while the high density lipid (HDL) content decreased. Bio-tea showed a higher preventive effect against myocardial infarction when compared to tea, as was observed by the significant reduction in heart weight, and blood glucose and increase in plasma albumin levels. Bio-tea significantly decreased cholesterol, triglycerides, LDL and VLDL while simultaneously increasing the levels of HDL. Similarly a decrease in leakage of cardiac markers from the myocardium was also observed.


Prevention of catheter-related blood stream infection: back to basics?
Central venous catheter (CVC)-related infections are a substantial problem in the intensive care unit (ICU). Our infection control team initiated the routine use of antiseptic-coated (chlorhexidine-silver sulfadiazine; Chx-SS) CVCs in our adult ICUs to reduce catheter-associated (CA) and catheter-related (CR) blood stream infection (BSI) as we implemented other educational and best practice standardization strategies. Prior randomized studies documented that the use of Chx-SS catheters reduces microbial colonization of the catheter compared with an uncoated standard (Std) CVC but does not reduce CR-BSI. We therefore implemented the routine use of uncoated Std CVCs in our surgical ICU (SICU) and examined the impact of this change. The use of uncoated Std CVCs does not increase CR-BSI rate in an SICU. Prospective evaluation of universal use of uncoated Std CVCs, implemented November 2007 in the SICU. The incidences of CA-BSI and CR-BSI were compared during November 2006-October 2007 (universal use of Chx-SS CVCs) and November 2007-October 2008 (universal use of Std CVCs) by t-test. The definitions of the U.S. Centers for Disease Control and Prevention were used for CA-BSI and CR-BSI. Patient data were collected via a dedicated Acute Physiology and Chronic Health Evaluation (APACHE) III coordinator for the SICU. Annual use of CVCs increased significantly in the last six years, from 3,543 (2001) to 5,799 (2006) total days. The APACHE III scores on day 1 increased from a mean of 54.4 in 2004 to 55.6 in 2008 (p = 0.0010; 95% confidence interval [CI] 1.29-5.13). The mean age of the patients was unchanged over this period, ranging from 58.2 to 59.6 years. The Chx-SS catheters were implemented in the SICU in 2002. Data regarding the specific incidence of CR-BSI were collected beginning at the end of 2005, with mandatory catheter tip cultures when CVCs were removed. Little difference was identified in the incidence of BSI between the interval with universal Chx-SS use and that with Std CVC use. (Total BSI 0.7 vs. 0.8 per 1,000 catheter days; CA-BSI 0.5 vs. 0.8 per 1,000 catheter days; CR-BSI 0.2 vs. 0 per 1,000 catheter days.) No difference was seen in the causative pathogens of CA-BSI or CR-BSI. Eliminating the universal use of Chx-SS-coated CVCs in an SICU with a low background incidence of CR-BSIs did not result in an increase in the rate of CR-BSIs. This study documents the greater importance of adherence to standardization of the processes of care related to CVC placement than of coated CVC use in the reduction of CR-BSI.


Strong top-down control in southern California kelp forest ecosystems.
Global-scale changes in anthropogenic nutrient input into marine ecosystems via terrestrial runoff, coupled with widespread predator removal via fishing, have created greater urgency for understanding the relative role of top-down versus bottom-up control of food web dynamics. Yet recent large-scale studies of community regulation in marine ecosystems have shown dramatically different results that leave this issue largely unresolved. We combined a multiyear, large-scale data set of species abundances for 46 species in kelp forests from the California Channel Islands with satellite-derived primary production and found that top-down control explains 7- to 10-fold more of the variance in abundance of bottom and mid-trophic levels than does bottom-up control. This top-down control was propagated via a variety of species-level direct and indirect responses to predator abundance. Management of top-down influences such as fishing may be more important in coastal marine ecosystems, particularly in kelp forest systems, than is commonly thought.


Cannabis use and risk of schizophrenia: a Mendelian randomization study.
Cannabis use is observationally associated with an increased risk of schizophrenia, but whether the relationship is causal is not known. Using a genetic approach, we took 10 independent genetic variants previously identified to associate with cannabis use in 32 330 individuals to determine the nature of the association between cannabis use and risk of schizophrenia. Genetic variants were employed as instruments to recapitulate a randomized controlled trial involving two groups (cannabis users vs nonusers) to estimate the causal effect of cannabis use on risk of schizophrenia in 34 241 cases and 45 604 controls from predominantly European descent. Genetically-derived estimates were compared with a meta-analysis of observational studies reporting ever use of cannabis and risk of schizophrenia or related disorders. Based on the genetic approach, use of cannabis was associated with increased risk of schizophrenia (odds ratio (OR) of schizophrenia for users vs nonusers of cannabis: 1.37; 95% confidence interval (CI), 1.09-1.67; P-value=0.007). The corresponding estimate from observational analysis was 1.43 (95% CI, 1.19-1.67; P-value for heterogeneity =0.76). The genetic markers did not show evidence of pleiotropic effects and accounting for tobacco exposure did not alter the association (OR of schizophrenia for users vs nonusers of cannabis, adjusted for ever vs never smoker: 1.41; 95% CI, 1.09-1.83). This adds to the substantial evidence base that has previously identified cannabis use to associate with increased risk of schizophrenia, by suggesting that the relationship is causal. Such robust evidence may inform public health messages about cannabis use, especially regarding its potential mental health consequences.


Effect of antibiotics on redox transformations of arsenic and diversity of arsenite-oxidizing bacteria in sediment microbial communities.
In the present study, we investigated the effect of antibiotics on microbial arsenate (As(V)) reduction and arsenite (As(III)) oxidation in sediments collected from a small pond and eutrophic lake. The As(V)-reducing activities were less susceptible to chloramphenicol in aerobic conditions than in anaerobic conditions. Aerobic As(V) reduction proceeded in the presence of diverse types of antibiotics, suggesting that As-resistant bacteria are widely antibiotic resistant. In contrast, some antibiotics, e.g., chloramphenicol, strongly inhibited aerobic As(III) oxidation. In addition, bacterial As(III) oxidase genes were scarcely amplified and Proteobacteria -related 16S rRNA genes drastically decreased in chloramphenicol-amended cultures. Erythromycin and lincomycin, which successfully target many Gram-positive bacteria, scarcely affected As(III) oxidation, although they decreased the diversity of As(III) oxidase genes. These results indicate that the aerobic As(III) oxidizers in the sediment cultures are mainly composed of Proteobacteria and are more sensitive to certain types of antibiotics than the aerobic As(V) reducers. Our results suggest that antibiotic disturbance of environmental microbial communities may affect the biogeochemical cycle of As.


Genistein inhibits NF-kappa B activation in prostate cancer cells.
Prostate cancer is the second leading cause of cancer-related deaths in men in the United States. Epidemiological studies indicate that susceptibility to prostate cancer may be partly due to environmental influences, especially diet. An association has been shown between decreased prostate cancer risk and mortality with increased consumption of soy products, resulting in increased levels of isoflavones. We previously demonstrated that the soy isoflavone genistein inhibits cell growth and induces apoptosis in prostate cancer cells. To further elucidate the molecular mechanism by which genistein elicits its apoptotic effect, we investigated the role of a transcription factor, nuclear factor-kappa B (NF-kappa B), in the androgen-sensitive cell line LNCaP and the androgen-insensitive cell line PC3. Here we show that genistein decreases NF-kappa B DNA binding and abrogates NF-kappa B activation by DNA-damaging agents, H2O2 and tumor necrosis factor-alpha, in prostate cancer cells regardless of androgen sensitivity. Additionally, we have demonstrated that genistein reduces phosphorylation of the inhibitory protein I kappa B alpha and blocks the nuclear translocation of NF-kappa B, prohibiting DNA binding and preventing NF-kappa B activation. These results provide a mechanism by which genistein induces apoptosis in prostate cancer cells: the inactivation of NF-kappa B. Furthermore, genistein's ability to abrogate NF-kappa B activation by DNA-damaging agents strongly supports genistein's role as a chemopreventive agent.


RocA Has Serotype-Specific Gene Regulatory and Pathogenesis Activities in Serotype M28 Group A Streptococcus.
Serotype M28 group A streptococcus (GAS) is a common cause of infections such as pharyngitis ("strep throat") and necrotizing fasciitis ("flesh-eating" disease). Relatively little is known about the molecular mechanisms underpinning M28 GAS pathogenesis. Whole-genome sequencing studies of M28 GAS strains recovered from patients with invasive infections found an unexpectedly high number of missense (amino acid-changing) and nonsense (protein-truncating) polymorphisms in rocA (regulator of Cov), leading us to hypothesize that altered RocA activity contributes to M28 GAS molecular pathogenesis. To test this hypothesis, an isogenic rocA deletion mutant strain was created. Transcriptome sequencing (RNA-seq) analysis revealed that RocA inactivation significantly alters the level of transcripts for 427 and 323 genes at mid-exponential and early stationary growth phases, respectively, including genes for 41 transcription regulators and 21 virulence factors. In contrast, RocA transcriptomes from other GAS M protein serotypes are much smaller and include fewer transcription regulators. The rocA mutant strain had significantly increased secreted activity of multiple virulence factors and grew to significantly higher colony counts under acid stress in vitro RocA inactivation also significantly increased GAS virulence in a mouse model of necrotizing myositis. Our results demonstrate that RocA is an important regulator of transcription regulators and virulence factors in M28 GAS and raise the possibility that naturally occurring polymorphisms in rocA in some fashion contribute to human invasive infections caused by M28 GAS strains.


Organoarsenicals in poultry litter: detection, fate, and toxicity.
Arsenic contamination in groundwater has endangered the health and safety of millions of people around the world. One less studied mechanism for arsenic introduction into the environment is the use of organoarsenicals in animal feed. Four organoarsenicals are commonly employed as feed additives: arsanilic acid, carbarsone, nitarsone, and roxarsone. Organoarsenicals are composed of a phenylarsonic acid molecule with substituted functional groups. This review documents the use of organoarsenicals in the poultry industry, reports analytical methods available for quantifying organic arsenic, discusses the fate and transport of organoarsenicals in environmental systems, and identifies toxicological concerns associated with these chemicals. In reviewing the literature on organoarsenicals, several research needs were highlighted: advanced analytical instrumentation that allows for identification and quantification of organoarsenical degradation products; a greater research emphasis on arsanilic acid, carbarsone, and nitarsone; identification of degradation pathways, products, and kinetics; and testing/development of agricultural wastewater and solid treatment technologies for organoarsenical-laden waste.


Stationary phase gene expression of Mycobacterium tuberculosis following a progressive nutrient depletion: a model for persistent organisms?
The majority of individuals infected with TB develop a latent infection, in which organisms survive within the body while evading the host immune system. Such persistent bacilli are capable of surviving several months of combinatorial antibiotic treatment. Evidence suggests that stationary phase bacteria adapt to increase their tolerance to environmental stresses. We have developed a unique in vitro model of dormancy based on the characterization of a single, large volume fermenter culture of M. tuberculosis, as it adapts to stationary phase. Cells are maintained in controlled and defined aerobic conditions (50% dissolved oxygen tension), using probes that measure dissolved oxygen tension, temperature, and pH. Microarray analysis has been used in conjunction with viability and nutrient depletion assays to dissect differential gene expression. Following exponential phase growth the gradual depletion of glucose/glycerol resulted in a small population of survivors that were characterized for periods in excess of 100 days. Bacilli adapting to nutrient depletion displayed characteristics associated with persistence in vivo, including entry into a non-replicative state and the up-regulation of genes involved in beta-oxidation of fatty acids and virulence. A reduced population of non-replicating bacilli went on to adapt sufficiently to re-initiate cellular division.


Evidence of a diverse T cell receptor repertoire for acetylcholine receptor, the autoantigen of myasthenia gravis.
We utilized two methods to look for T cell clonal expansions in myasthenia gravis (MG). We analyzed TCRBV CDR3 length polymorphism (spectratyping) to look for evidence of clonal expansion of CD4 or CD8 T cells directly from peripheral blood of MG patients. No statistically significant differences were found between the diversity of TCR repertoires in MG patients compared to normal control individuals when analyzed as groups. Rare oligoclonal expansions were detected in some individual MG patients but the significance of these findings is unclear. Next, we analyzed a panel of T cell hybridomas from acetylcholine receptor (AChR) immunized, MG-susceptible HLA-DR3 transgenic mice. The epitope specificity, TCRBV gene usage and CDR3 sequences of these hybridomas were highly diverse. We conclude there is only limited evidence for restricted TCR repertoire usage in human MG and suggest this may be due to the inability of HLA-DR molecules to select for restricted TCR recognition of AChR epitopes.


HIV among people who inject drugs in the Middle East and North Africa: systematic review and data synthesis.
It is perceived that little is known about the epidemiology of HIV infection among people who inject drugs (PWID) in the Middle East and North Africa (MENA). The primary objective of this study was to assess the status of the HIV epidemic among PWID in MENA by describing HIV prevalence and incidence. Secondary objectives were to describe the risk behavior environment and the HIV epidemic potential among PWID, and to estimate the prevalence of injecting drug use in MENA. This was a systematic review following the PRISMA guidelines and covering 23 MENA countries. PubMed, Embase, regional and international databases, as well as country-level reports were searched up to December 16, 2013. Primary studies reporting (1) the prevalence/incidence of HIV, other sexually transmitted infections, or hepatitis C virus (HCV) among PWIDs; or (2) the prevalence of injecting or sexual risk behaviors, or HIV knowledge among PWID; or (3) the number/proportion of PWID in MENA countries, were eligible for inclusion. The quality, quantity, and geographic coverage of the data were assessed at country level. Risk of bias in predefined quality domains was described to assess the quality of available HIV prevalence measures. After multiple level screening, 192 eligible reports were included in the review. There were 197 HIV prevalence measures on a total of 58,241 PWID extracted from reports, and an additional 226 HIV prevalence measures extracted from the databases. We estimated that there are 626,000 PWID in MENA (range: 335,000-1,635,000, prevalence of 0.24 per 100 adults). We found evidence of HIV epidemics among PWID in at least one-third of MENA countries, most of which are emerging concentrated epidemics and with HIV prevalence overall in the range of 10%-15%. Some of the epidemics have however already reached considerable levels including some of the highest HIV prevalence among PWID globally (87.1% in Tripoli, Libya). The relatively high prevalence of sharing needles/syringes (18%-28% in the last injection), the low levels of condom use (20%-54% ever condom use), the high levels of having sex with sex workers and of men having sex with men (15%-30% and 2%-10% in the last year, respectively), and of selling sex (5%-29% in the last year), indicate a high injecting and sexual risk environment. The prevalence of HCV (31%-64%) and of sexually transmitted infections suggest high levels of risk behavior indicative of the potential for more and larger HIV epidemics. Our study identified a large volume of HIV-related biological and behavioral data among PWID in the MENA region. The coverage and quality of the data varied between countries. There is robust evidence for HIV epidemics among PWID in multiple countries, most of which have emerged within the last decade and continue to grow. The lack of sufficient evidence in some MENA countries does not preclude the possibility of hidden epidemics among PWID in these settings. With the HIV epidemic among PWID in overall a relatively early phase, there is a window of opportunity for prevention that should not be missed through the provision of comprehensive programs, including scale-up of harm reduction services and expansion of surveillance systems.


In situ detection and identification of hair dyes using surface-enhanced Raman spectroscopy (SERS).
Hair is one of the most common types of physical evidence found at a crime scene. Forensic examination may suggest a connection between a suspect and a crime scene or victim, or it may demonstrate an absence of such associations. Therefore, forensic analysis of hair evidence is invaluable to criminal investigations. Current hair forensic examinations are primarily based on a subjective microscopic comparison of hair found at the crime scene with a sample of suspect's hair. Since this is often inconclusive, the development of alternative and more-accurate hair analysis techniques is critical. In this study, we utilized surface-enhanced Raman spectroscopy (SERS) to demonstrate that artificial dyes can be directly detected on hair. This spectroscopic technique is capable of a confirmatory identification of analytes with single molecule resolution, requires minimal sample, and has the advantage of fluorescence quenching. Our study reveals that SERS can (1) identify whether hair was artificially dyed or not, (2) determine if a permanent or semipermanent colorants were used, and (3) distinguish the commercial brands that are utilized to dye hair. Such analysis is rapid, minimally destructive, and can be performed directly at the crime scene. This study provides a novel perspective of forensic investigations of hair evidence.


DNA demethylation is initiated in the central cells of Arabidopsis and rice.
Cytosine methylation is a DNA modification with important regulatory functions in eukaryotes. In flowering plants, sexual reproduction is accompanied by extensive DNA demethylation, which is required for proper gene expression in the endosperm, a nutritive extraembryonic seed tissue. Endosperm arises from a fusion of a sperm cell carried in the pollen and a female central cell. Endosperm DNA demethylation is observed specifically on the chromosomes inherited from the central cell in Arabidopsis thaliana, rice, and maize, and requires the DEMETER DNA demethylase in Arabidopsis DEMETER is expressed in the central cell before fertilization, suggesting that endosperm demethylation patterns are inherited from the central cell. Down-regulation of the MET1 DNA methyltransferase has also been proposed to contribute to central cell demethylation. However, with the exception of three maize genes, central cell DNA methylation has not been directly measured, leaving the origin and mechanism of endosperm demethylation uncertain. Here, we report genome-wide analysis of DNA methylation in the central cells of Arabidopsis and rice-species that diverged 150 million years ago-as well as in rice egg cells. We find that DNA demethylation in both species is initiated in central cells, which requires DEMETER in Arabidopsis However, we do not observe a global reduction of CG methylation that would be indicative of lowered MET1 activity; on the contrary, CG methylation efficiency is elevated in female gametes compared with nonsexual tissues. Our results demonstrate that locus-specific, active DNA demethylation in the central cell is the origin of maternal chromosome hypomethylation in the endosperm.


Genotypic differences and prior defoliation affect re-growth and phytochemistry after coppicing in Populus tremuloides.
Although considerable research has explored how tree growth and defense can be influenced by genotype, the biotic environment, and their interaction, little is known about how genotypic differences, prior defoliation, and their interactive effects persist in trees that re-grow after damage that severs their primary stem. To address these issues, we established a common garden consisting of twelve genotypes of potted aspen (Populus tremuloides) trees, and subjected half of the trees to defoliation in two successive years. At the beginning of the third year, all trees were severed at the soil surface (coppiced) and allowed to regenerate for five months. Afterwards, we counted the number of root and stump sprouts produced and measured the basal diameter (d) and height (h) of the tallest ramet in each pot. We collected leaves one and two years after the second defoliation and assessed levels of phenolic glycosides, condensed tannins, and nitrogen. In terms of re-growth, we found that the total number of sprouts produced varied by 3.6-fold among genotypes, and that prior defoliation decreased total sprout production by 24%. The size (d(2)h) of ramets, however, did not differ significantly among genotypes or defoliation classes. In terms of phytochemistry, we observed genotypic differences in concentrations of all phytochemicals assessed both one and two years after the second defoliation. Two years after defoliation, we observed effects of prior defoliation in a genotype-by-defoliation interaction for condensed tannins. Results from this study demonstrate that genotypic differences and impacts of prior defoliation persist to influence growth and defense traits in trees even after complete removal of above-ground stems, and thus likely influence productivity and plant-herbivore interactions in forests affected by natural disturbances or actively managed through coppicing.


An alien divalent ion reveals a major role for Ca²⁺ buffering in controlling slow transmitter release.
Ca(2+)-dependent transmitter release occurs in a fast and in a slow phase, but the differential roles of Ca(2+) buffers and Ca(2+) sensors in shaping release kinetics are still controversial. Replacing extracellular Ca(2+) by Sr(2+) causes decreased fast release but enhanced slow release at many synapses. Here, we established presynaptic Sr(2+) uncaging and made quantitative Sr(2+)- and Ca(2+)-imaging experiments at the mouse calyx of Held synapse, to reveal the interplay between Ca(2+) sensors and Ca(2+) buffers in the control of fast and slow release. We show that Sr(2+) activates the fast, Synaptotagmin-2 (Syt2) sensor for vesicle fusion with sixfold lower affinity but unchanged high cooperativity. Surprisingly, Sr(2+) also activates the slow sensor that remains in Syt2 knock-out synapses with a lower efficiency, and Sr(2+) was less efficient than Ca(2+) in the limit of low concentrations in wild-type synapses. Quantitative imaging experiments show that the buffering capacity of the nerve terminal is markedly lower for Sr(2+) than for Ca(2+) (~5-fold). This, together with an enhanced Sr(2+) permeation through presynaptic Ca(2+) channels (~2-fold), admits a drastically higher spatially averaged Sr(2+) transient compared with Ca(2+). Together, despite the lower affinity of Sr(2+) at the fast and slow sensors, the massively higher amplitudes of spatially averaged Sr(2+) transients explain the enhanced late release. This also allows us to conclude that Ca(2+) buffering normally controls late release and prevents the activation of the fast release sensor by residual Ca(2+).


Collectors on illicit collecting: Higher loyalties and other techniques of neutralization in the unlawful collecting of rare and precious orchids and antiquities.
Trafficking natural objects and trafficking cultural objects have been treated separately both in regulatory policy and in criminological discussion. The former is generally taken to be 'wildlife crime' while the latter has come to be considered under the auspices of a debate on 'illicit art and antiquities'. In this article we study the narrative discourse of high-end collectors of orchids and antiquities. The illicit parts of these global trades are subject to this analytical divide between wildlife trafficking and art trafficking, and this has resulted in quite different regulatory structures for each of these markets. However, the trafficking routines, the types and levels of harm involved, and the supply-demand dynamics in the trafficking of orchids and antiquities are actually quite similar, and in this study we find those structural similarities reflected in substantial common ground in the way collectors talk about their role in each market. Collectors of rare and precious orchids and antiquities valorize their participation in markets that are known to be in quite considerable degree illicit, appealing to 'higher loyalties' such as preservation, appreciation of aesthetic beauty and cultural edification. These higher loyalties, along with other techniques of neutralization, deplete the force of law as a guide to appropriate action. We propose that the appeal to higher loyalties is difficult to categorize as a technique of neutralization in this study as it appears to be a motivational explanation for the collectors involved. The other classic techniques of neutralization are deflective, guilt and critique reducing narrative mechanisms, while higher loyalties drives illicit behaviour in collecting markets for orchids and antiquities in ways that go significantly beyond the normal definition of neutralization.


Neutrophil extracellular traps exacerbate neurological deficits after traumatic brain injury.
Traumatic brain injury (TBI) is a major cause of mortality and morbidity. Preventative measures reduce injury incidence and/or severity, yet one-third of hospitalized patients with TBI die from secondary pathological processes that develop during supervised care. Neutrophils, which orchestrate innate immune responses, worsen TBI outcomes via undefined mechanisms. We hypothesized that formation of neutrophil extracellular traps (NETs), a purported mechanism of microbial trapping, exacerbates acute neurological injury after TBI. NET formation coincided with cerebral hypoperfusion and tissue hypoxia after experimental TBI, while elevated circulating NETs correlated with reduced serum deoxyribonuclease-1 (DNase-I) activity in patients with TBI. Functionally, Toll-like receptor 4 (TLR4) and the downstream kinase peptidylarginine deiminase 4 (PAD4) mediated NET formation and cerebrovascular dysfunction after TBI. Last, recombinant human DNase-I degraded NETs and improved neurological function. Thus, therapeutically targeting NETs may provide a mechanistically innovative approach to improve TBI outcomes without the associated risks of global neutrophil depletion.


Characterization of complex polysorbate formulations by means of shape-selective mass spectrometry.
Complex synthetic formulations based on polysorbates can be challenging to characterize. They may be composed of many similar products including those of the same molecular weight, which cannot be readily separated by separation science approaches. Carbon number variation and ethylene oxide distribution add to the complexity. The properties of these formulations will be dependent on the chemical structure and relative concentration of formulation components. Here we describe the use of two experimental approaches based on mass spectrometry to provide enhanced characterization of these formulations. The first utilizes an atmospheric pressure solids analysis probe to rapidly determine the percentage content of individual esters in a formulation. These are shown to be in good agreement with product specification sheets. In a second approach, mobility separation has been integrated into a MALDI-MS/MS experiment to categorize major, minor, and trace ingredients. Components of identical molecular mass in the polysorbate formulations have been separated by ion mobility and then fragmented for additional characterization. The rapidity and level of structural detail provided by these experiments offers a significant opportunity to develop practical screening methods for complex formulations.


Variant Profiling of Candidate Genes in Pancreatic Ductal Adenocarcinoma.
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis. Variant profiling is crucial for developing personalized treatment and elucidating the etiology of this disease. Patients with PDAC undergoing surgery from 2007 to 2012 (n = 73) were followed from diagnosis until death or the end of the study. We applied an anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) method to a panel of 65 selected genes and assessed analytical performance by sequencing a quantitative multiplex DNA reference standard. In clinical PDAC samples, detection of low-level KRAS (Kirsten rat sarcoma viral oncogene homolog) mutations was validated by allele-specific PCR and digital PCR. We compared overall survival of patients according to KRAS mutation status by log-rank test and applied logistic regression to evaluate the association between smoking and tumor variant types. The AMP-based NGS method could detect variants with allele frequencies as low as 1% given sufficient sequencing depth (>1500×). Low-frequency KRAS G12 mutations (allele frequency 1%-5%) were all confirmed by allele-specific PCR and digital PCR. The most prevalent genetic alterations were in KRAS (78% of patients), TP53 (tumor protein p53) (25%), and SMAD4 (SMAD family member 4) (8%). Overall survival in T3-stage PDAC patients differed among KRAS mutation subtypes (P = 0.019). Transversion variants were more common in ever-smokers than in never-smokers (odds ratio 5.7; 95% CI 1.2-27.8). The AMP-based NGS method is applicable for profiling tumor variants. Using this approach, we demonstrated that in PDAC patients, KRAS mutant subtype G12V is associated with poorer survival, and that transversion variants are more common among smokers.


Genetic load makes cancer cells more sensitive to common drugs: evidence from Cancer Cell Line Encyclopedia.
Genetic alterations initiate tumors and enable the evolution of drug resistance. The pro-cancer view of mutations is however incomplete, and several studies show that mutational load can reduce tumor fitness. Given its negative effect, genetic load should make tumors more sensitive to anticancer drugs. Here, we test this hypothesis across all major types of cancer from the Cancer Cell Line Encyclopedia, which provides genetic and expression data of 496 cell lines together with their response to 24 common anticancer drugs. We found that the efficacy of 9 out of 24 drugs showed significant association with genetic load in a pan-cancer analysis. The associations for some tissue-drug combinations were remarkably strong, with genetic load explaining up to 83% of the variance in the drug response. Overall, the role of genetic load depended on both the drug and the tissue type with 10 tissues being particularly vulnerable to genetic load. We also identified changes in gene expression associated with increased genetic load, which included cell-cycle checkpoints, DNA damage and apoptosis. Our results show that genetic load is an important component of tumor fitness and can predict drug sensitivity. Beyond being a biomarker, genetic load might be a new, unexplored vulnerability of cancer.


A lack of consistent evidence for cortisol dysregulation in premenstrual syndrome/premenstrual dysphoric disorder.
Although decades of research has examined the association between cortisol regulation and premenstrual syndrome/premenstrual dysphoric disorder (PMS/PMDD), no review exists to provide a general set of conclusions from the extant research. In the present review we summarize and interpret research that has tested for associations between PMS/PMDD and cortisol levels and reactivity (n=38 original research articles). Three types of studies are examined: correlational studies, environmental-challenge studies, and pharmacological-challenge studies. Overall, there was very little evidence that women with and without PMS/PMDD demonstrate systematic and predictable mean-level differences in cortisol, or differences in cortisol response/reactivity to challenges. Methodological differences in sample size, the types of symptoms used for diagnosis (physical and psychological vs. only affective), or the type of cortisol measure used (serum vs. salivary), did not account for differences between studies that did and did not find significant effects. Caution is recommended before accepting the conclusion of null effects, and recommendations are made that more rigorous research be conducted, considering symptom-specificity, within-person analyses, and multiple parameters of cortisol regulation, before final conclusions are drawn.


Determination of ED50 values for praziquantel in praziquantel-resistant and -susceptible Schistosoma mansoni isolates.
The dose of praziquantel required to kill 50% of adult worms in vivo (i.e. the ED50) was estimated for nine different isolates of Schistosoma mansoni in infected mice. Four of the isolates were selected because they had not knowingly been in contact with the drug (i.e. they were putatively praziquantel-susceptible). Five putatively praziquantel-resistant isolates were chosen because they had been selectively bred for drug-resistance in the laboratory and/or had previously been shown to be relatively resistant to praziquantel in the field. The work was performed in three laboratories in different countries using pre-agreed and comparable experimental protocols. All four praziquantel-susceptible isolates had ED50s estimated to be <100 mg/kg (mean=70+/-7 SD; median=68), while all five putatively praziquantel-resistant isolates had estimated ED50s >100 mg/kg (mean=209+/-48 SD; median=192). Thus, the five praziquantel-resistant isolates, including two that had been subjected to drug pressure during more than 20 passages in mice, had drug ED50s that were approximately three times as great as those of the praziquantel-susceptible isolates. Two of the five isolates in the putatively resistant group had previously been passaged 15 or more times in mice without administration of drug-pressure, but had ED50s consistent with the other three isolates in the group, indicating that the trait of praziquantel-resistance did not necessarily impair biological fitness during laboratory passage. The protocols used here to estimate the praziquantel ED50s of S. mansoni isolates should be useful for establishing and monitoring the drug susceptibility/resistance profiles of parasite isolates freshly obtained from endemic areas, particularly those in which increased usage of the drug is likely to occur.


Effects of plasma fluoride and dietary calcium concentrations on GI absorption and secretion of fluoride in the rat.
This 30-day balance study with weanling rats was designed to determine the effects of plasma fluoride and dietary calcium concentration and their interaction on the absorption, balance, and tissue concentrations of fluoride. The three major groups differed according to the total exposure and plasma concentrations of fluoride. One group received fluoride only in the diet and the other two received additional fluoride by continuous infusion from miniosmotic pumps implanted S.C. Each group was divided into two subgroups with dietary calcium concentrations of 0.4% or 1.4%. Fluoride intake with the diet did not differ among the groups. Fecal fluoride excretion was directly related to plasma fluoride concentration. The absorption and balance of dietary fluoride were inversely related to plasma fluoride concentration. These effects were greatest in the groups fed the 1.4% calcium diet. The interactions of plasma fluoride and dietary calcium on these variables were highly significant (P < 0.0001). The balance of dietary fluoride was negative in the four groups that received additional fluoride by infusion. In the two groups that received fluoride only in the diet, the plasma and bone fluoride concentrations were 41% and 59% lower, respectively, in the 1.4% dietary calcium group. The findings indicate that net fluoride secretion into the GI tract can occur when plasma fluoride concentrations and calcium intake are elevated. They suggest that elevated plasma fluoride levels and calcium intake are factors that may diminish the effect of oral fluoride treatment in osteoporotic patients.


EPAS1 Gain-of-Function Mutation Contributes to High-Altitude Adaptation in Tibetan Horses.
High altitude represents some of the most extreme environments worldwide. The genetic changes underlying adaptation to such environments have been recently identified in multiple animals but remain unknown in horses. Here, we sequence the complete genome of 138 domestic horses encompassing a whole altitudinal range across China to uncover the genetic basis for adaptation to high-altitude hypoxia. Our genome data set includes 65 lowland animals across ten Chinese native breeds, 61 horses living at least 3,300 m above sea level across seven locations along Qinghai-Tibetan Plateau, as well as 7 Thoroughbred and 5 Przewalski's horses added for comparison. We find that Tibetan horses do not descend from Przewalski's horses but were most likely introduced from a distinct horse lineage, following the emergence of pastoral nomadism in Northwestern China ∼3,700 years ago. We identify that the endothelial PAS domain protein 1 gene (EPAS1, also HIF2A) shows the strongest signature for positive selection in the Tibetan horse genome. Two missense mutations at this locus appear strongly associated with blood physiological parameters facilitating blood circulation as well as oxygen transportation and consumption in hypoxic conditions. Functional validation through protein mutagenesis shows that these mutations increase EPAS1 stability and its hetero dimerization affinity to ARNT (HIF1B). Our study demonstrates that missense mutations in the EPAS1 gene provided key evolutionary molecular adaptation to Tibetan horses living in high-altitude hypoxic environments. It reveals possible targets for genomic selection programs aimed at increasing hypoxia tolerance in livestock and provides a textbook example of evolutionary convergence across independent mammal lineages.


Military veteran mortality following a survived suicide attempt.
Suicide is a global public health problem. Recently in the U.S., much attention has been given to preventing suicide and other premature mortality in veterans returning from Iraq and Afghanistan. A strong predictor of suicide is a past suicide attempt, and suicide attempters have multiple physical and mental comorbidities that put them at risk for additional causes of death. We examined mortality among U.S. military veterans after hospitalization for attempted suicide. A retrospective cohort study was conducted with all military veterans receiving inpatient treatment during 1993-1998 at United States Veterans Affairs (VA) medical facilities following a suicide attempt. Deaths occurring during 1993-2002, the most recent available year at the time, were identified through VA Beneficiary and Records Locator System data and National Death Index data. Mortality data for the general U.S. adult population were also obtained from the National Center for Health Statistics. Comparisons within the veteran cohort, between genders, and against the U.S. population were conducted with descriptive statistics and standardized mortality ratios. The actuarial method was used estimate the proportion of veterans in the cohort we expect would have survived through 2002 had they experienced the same rate of death that occurred over the study period in the U.S. population having the age and sex characteristics. During 1993-1998, 10,163 veterans were treated and discharged at a VA medical center after a suicide attempt (mean age = 44 years; 91% male). There was a high prevalence of diagnosed alcohol disorder or abuse (31.8%), drug dependence or abuse (21.8%), psychoses (21.2%), depression (18.5%), and hypertension (14.2%). A total of 1,836 (18.1%) veterans died during follow up (2,941.4/100,000 person years). The cumulative survival probability after 10 years was 78.0% (95% CI = 72.9, 83.1). Hence the 10-year cumulative mortality risk was 22.0%, which was 3.0 times greater than expected. The leading causes overall were heart disease (20.2%), suicide (13.1%), and unintentional injury (12.7%). Whereas suicide was the ninth leading cause of death in the U.S. population overall (1.8%) during the study period, suicide was the leading and second leading cause among women (25.0%) and men (12.7%) in the cohort, respectively. Veterans who have attempted suicide face elevated risks of all-cause mortality with suicide being prominent. This represents an important population for prevention activities.


Serum Polyunsaturated Fatty Acid Composition and Serum High-Sensitivity C-Reactive Protein Levels in Healthy Japanese Residents: The KOBE Study.
Serum polyunsaturated fatty acid (PUFA) composition reflects dietary intake and is related to risks for cardiovascular diseases. We hypothesized that serum n-3 PUFA composition, especially including long-chain n-3 PUFA such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), is associated with inflammatory status, which is related to increased risk for cardiovascular diseases. We investigated the relationship between serum PUFA composition and high-sensitivity C-reactive protein (hs-CRP) levels in a cross-sectional study among 1,102 healthy men and women aged 40-74 years who reside in Kobe City. Multiple linear regression models that predict hs-CRP level were prepared to confirm the contribution of serum total n-3 PUFA, long-chain n-3 PUFA, EPA and DHA compositions after adjusting for other PUFAs and atherosclerotic risk factors. The serum n-3 PUFA, particularly long-chain n-3 PUFA, compositions were inversely associated with the hs-CRP levels. The standardized regression coefficient was -0.089 (p < 0.01) for total n-3 PUFA, -0.091 (p < 0.01) for long-chain n-3 PUFA, -0.071 (p = 0.03) for EPA, and -0.068 (p = 0.04) for DHA. The n-6 PUFA compositions were also inversely associated with the hs-CRP levels (-0.169 [p < 0.01] for total n-6 PUFA and -0.159 [p < 0.01] for linoleic acid). The serum n-3 PUFA compositions were inversely related with the hs-CRP levels, similar associations were also observed in n-6 PUFA compositions. Our results suggest that dietary PUFA intake was inversely associated with attenuated inflammation in healthy Japanese population.


RNA-Seq Atlas of Glycine max: a guide to the soybean transcriptome.
Next generation sequencing is transforming our understanding of transcriptomes. It can determine the expression level of transcripts with a dynamic range of over six orders of magnitude from multiple tissues, developmental stages or conditions. Patterns of gene expression provide insight into functions of genes with unknown annotation. The RNA Seq-Atlas presented here provides a record of high-resolution gene expression in a set of fourteen diverse tissues. Hierarchical clustering of transcriptional profiles for these tissues suggests three clades with similar profiles: aerial, underground and seed tissues. We also investigate the relationship between gene structure and gene expression and find a correlation between gene length and expression. Additionally, we find dramatic tissue-specific gene expression of both the most highly-expressed genes and the genes specific to legumes in seed development and nodule tissues. Analysis of the gene expression profiles of over 2,000 genes with preferential gene expression in seed suggests there are more than 177 genes with functional roles that are involved in the economically important seed filling process. Finally, the Seq-atlas also provides a means of evaluating existing gene model annotations for the Glycine max genome. This RNA-Seq atlas extends the analyses of previous gene expression atlases performed using Affymetrix GeneChip technology and provides an example of new methods to accommodate the increase in transcriptome data obtained from next generation sequencing. Data contained within this RNA-Seq atlas of Glycine max can be explored at http://www.soybase.org/soyseq.


Regional blood flow distribution from the proximal arterial cannula during veno-arterial extracorporeal membrane oxygenation in neonatal dog.
Extracorporeal membrane oxygenation (ECMO) is frequently used for treatment of patients with severe hypoxemia due to life-threatening respiratory failure. Due to this hypoxemia, the myocardium of these patients is insufficiently provided with oxygen, and consequently their cardiac function commonly deteriorates. But veno-arterial (V-A) ECMO provides oxygenated blood to the coronary arteries from ECMO circuit insufficiently. To increase the coronary blood flow distributed from ECMO, we placed the arterial cannula 1 cm above the aortic valve and evaluated the regional blood from the proximal arterial cannula in comparison with the distal cannula. Eight neonatal dogs weighting 1.8-2.5 kg were supported by V-A ECMO. The regional blood flow from the arterial cannula was measured by injection of colored microspheres into ECMO circuit. The site of the arterial cannula was changed under fluoroscopy. The bypass flow was maintained at either 50 or 100 ml/min/kg. We found that the coronary blood flow distributed from the proximal arterial cannula was significantly higher than that from the distal cannula. The proximal arterial cannula appears necessary to provide sufficient oxygenated blood to the coronary circulation during V-A ECMO. Therefore, it is expected that the increased cardiac function may improved, and that the survival rate of the patients with retarded cardiac function due to severe hypoxemia may increase by proximal placement of the arterial cannula during V-A ECMO.


Impact of lipid-based nutrient supplementation (LNS) on children's diet adequacy in Western Uganda.
Lipid-based nutrient supplements (LNS) can help treat undernutrition; however, the dietary adequacy of children supplemented with LNS, and household utilisation patterns are not well understood. We assessed diet adequacy and the quality of complementary foods by conducting a diet assessment of 128 Ugandan children, ages 6-59 months, who participated in a 10-week programme for children with moderate acute malnutrition (MAM, defined as weight-for-age z-score < -2). Caregivers were given a weekly ration of 650 kcal day(-1) (126 g day(-1) ) of a peanut/soy LNS. Two 24-h dietary recalls were administered per child. LNS was offered to 86% of targeted children at least once. Among non-breastfed children, over 90% met their estimated average requirement (EAR) cut-points for all examined nutrients. Over 90% of breastfed children met EAR cut-points for nutrient density for most nutrients, except for zinc where 11.7% met cut-points. A lower proportion of both breastfed and non-breastfed children met adjusted EARs for the specific nutritional needs of MAM. Fewer than 20% of breastfed children met EAR nutrient-density guidelines for MAM for zinc, vitamin C, vitamin A and folate. Underweight status, the presence of a father in the child's home, and higher programme attendance were all associated with greater odds of feeding LNS to targeted children. Children in this community-based supplemental feeding programme who received a locally produced LNS exhibited substantial micronutrient deficiencies given the special dietary needs of this population. These results can help inform programme strategies to improve LNS targeting, and highlight potential nutrient inadequacies for consumers of LNS in community-based settings.


Thrombospondin signaling through the calreticulin/LDL receptor-related protein co-complex stimulates random and directed cell migration.
The matricellular extracellular matrix protein thrombospondin-1 (TSP1) stimulates focal adhesion disassembly through a sequence (known as the hep I peptide) in its heparin-binding domain. This mediates signaling through a receptor co-complex involving calreticulin and low-density lipoprotein (LDL) receptor-related protein (LRP). We postulate that this transition to an intermediate adhesive state enhances cellular responses to dynamic environmental conditions. Since cell adhesion dynamics affect cell motility, we asked whether TSP1/hep I-induced intermediate adhesion alters cell migration. Using both transwell and Dunn chamber assays, we demonstrate that TSP1 and hep I gradients stimulate endothelial cell chemotaxis. Treatment with focal adhesion-labilizing concentrations of TSP1/hep I in the absence of a gradient enhances endothelial cell random migration, or chemokinesis, associated with an increase in cells migrating, migration speed, and total cellular displacement. Calreticulin-null and LRP-null fibroblasts do not migrate in response to TSP1/hep I, nor do endothelial cells treated with the LRP inhibitor receptor-associated protein (RAP). Furthermore, TSP1/hep I-induced focal adhesion disassembly is associated with reduced chemotaxis to basic fibroblast growth factor (bFGF) but enhanced chemotaxis to acidic (a)FGF, suggesting differential modulation of growth factor-induced migration. Thus, TSP1/hep I stimulation of intermediate adhesion regulates the migratory phenotype of endothelial cells and fibroblasts, suggesting a role for TSP1 in remodeling responses.


Assessing the Complex and Evolving Relationship between Charges and Payments in US Hospitals: 1996 - 2012.
In 2013 the United States spent $2.9 trillion on health care, more than in any previous year. Much of the debate around slowing health care spending growth focuses on the complicated pricing system for services. Our investigation contributes to knowledge of health care spending by assessing the relationship between charges and payments in the inpatient hospital setting. In the US, charges and payments differ because of a complex set of incentives that connect health care providers and funders. Our methodology can also be applied to adjust charge data to reflect actual spending. We extracted cause of health care encounter (cause), primary payer (payer), charge, and payment information for 50,172 inpatient hospital stays from 1996 through 2012. We used linear regression to assess the relationship between charges and payments, stratified by payer, year, and cause. We applied our estimates to a large, nationally representative hospital charge sample to estimate payments. The average amount paid per $1 charged varies significantly across three dimensions: payer, year, and cause. Among the 10 largest causes of health care spending, average payments range from 23 to 55 cents per dollar charged. Over time, the amount paid per dollar charged is decreasing for those with private or public insurance, signifying that inpatient charges are increasing faster than the amount insurers pay. Conversely, the amount paid by out-of-pocket payers per dollar charged is increasing over time for several causes. Applying our estimates to a nationally representative hospital charge sample generates payment estimates which align with the official US estimates of inpatient spending. The amount paid per $1 charged fluctuates significantly depending on the cause of a health care encounter and the primary payer. In addition, the amount paid per charge is changing over time. Transparent accounting of hospital spending requires a detailed assessment of the substantial and growing gap between charges and payments. Understanding what is driving this divergence and generating accurate spending estimates can inform efforts to contain health care spending.


Haptic and Tactile Adjectives Are Consistently Mapped onto Color Space.
Cross-modal associations refer to non-arbitrary associations of features across sensory modalities. Such associations have been observed between many different sensory features. One association that has rarely been studied so far is between touch and color. In this study, participants were asked to match tactile and haptic adjectives to color samples shown individually on a screen. They could select one to 11 tactile and haptic terms, presented in 11 pairs of opposed adjectives. The results showed a regular pattern in the way tactile and haptic terms were matched to color. Our results further revealed that the colors to which tactile and haptic terms were matched did not fall within the boundaries of color lexical categories, suggesting that the associations were not based on lexicon--despite the frequent occurrence of linguistic expressions such as 'soft pink', not all colors called 'pink' were matched to 'soft'. In contrast with one recent study, the distribution of tactile and haptic terms across the Munsell array suggests that along with brightness and chroma, hue was also relevant to participants' responses. Specifically in the case of hue, several opposed adjectives were relatively well matched to opposed colors, along the orthogonal Yellow/Blue and Red/Green axes, which are suggested to structure the space of hue experience. Possible accounts of these results are considered.


Genetic architecture of sporadic frontotemporal dementia and overlap with Alzheimer's and Parkinson's diseases.
Clinical, pathological and genetic overlap between sporadic frontotemporal dementia (FTD), Alzheimer's disease (AD) and Parkinson's disease (PD) has been suggested; however, the relationship between these disorders is still not well understood. Here we evaluated genetic overlap between FTD, AD and PD to assess shared pathobiology and identify novel genetic variants associated with increased risk for FTD. Summary statistics were obtained from the International FTD Genomics Consortium, International PD Genetics Consortium and International Genomics of AD Project (n>75 000 cases and controls). We used conjunction false discovery rate (FDR) to evaluate genetic pleiotropy and conditional FDR to identify novel FTD-associated SNPs. Relevant variants were further evaluated for expression quantitative loci. We observed SNPs within the HLA, MAPT and APOE regions jointly contributing to increased risk for FTD and AD or PD. By conditioning on polymorphisms associated with PD and AD, we found 11 loci associated with increased risk for FTD. Meta-analysis across two independent FTD cohorts revealed a genome-wide signal within the APOE region (rs6857, 3'-UTR=PVRL2, p=2.21×10-12), and a suggestive signal for rs1358071 within the MAPT region (intronic=CRHR1, p=4.91×10-7) with the effect allele tagging the H1 haplotype. Pleiotropic SNPs at the HLA and MAPT loci associated with expression changes in cis-genes supporting involvement of intracellular vesicular trafficking, immune response and endo/lysosomal processes. Our findings demonstrate genetic pleiotropy in these neurodegenerative diseases and indicate that sporadic FTD is a polygenic disorder where multiple pleiotropic loci with small effects contribute to increased disease risk.


Minimal shortening in a high-frequency muscle.
Reducing the cost of high-frequency muscle contractions can be accomplished by minimizing cross-bridge cycling or by recycling elastic strain energy. Energy saving by contractile minimization has very different implications for muscle strain and activation patterns than by elastic recoil. Minimal cross-bridge cycling will be reflected in minimal contractile strains and highly reduced force, work and power output, whereas elastic energy storage requires a period of active lengthening that increases mechanical output. In this study, we used sonomicrometry and electromyography to test the relative contributions of energy reduction and energy recycling strategies in the tailshaker muscles of western diamondback rattlesnakes (Crotalus atrox). We found that tailshaker muscle contractions produce a mean strain of 3%, which is among the lowest strains ever recorded in vertebrate muscle during movement. The relative shortening velocities (V/V(max)) of 0.2-0.3 were in the optimal range for maximum power generation, indicating that the low power output reported previously for tailshaker muscle is due mainly to contractile minimization rather than to suboptimal V/V(max). In addition, the brief contractions (8-18 ms) had only limited periods of active lengthening (0.2-0.5 ms and 0.002-0.035%), indicating little potential for elastic energy storage and recoil. These features indicate that high-frequency muscles primarily reduce metabolic energy input rather than recycle mechanical energy output.


Periodontal repair in dogs: effect of wound stabilization on healing.
This study evaluated a biodegradable polylactic acid matrix as a wound stabilizing implant in reconstructive periodontal surgery. Supra-alveolar circumferential periodontal defects, 5 to 6 mm large, were surgically created around the mandibular premolars in 7 beagle dogs. The root surfaces in left and right jaw quadrants were treated with either heparin or saline. In this model, root surface treatment with heparin compromises periodontal repair and results in a long junctional epithelium and a reduced connective tissue repair to the root surface, whereas saline treatment results in almost complete connective tissue repair. Following heparin or saline treatment a polylactic acid implant was placed on 1 premolar in each quadrant. After 4 weeks of wound healing, the dogs were sacrificed and tissue blocks prepared for histometric analysis. Postoperatively, the implant became exposed and infected in 3 dogs and had to be removed. Therefore, the results reflect the 4 dogs in which healing progressed uneventfully. Connective tissue repair to the root surface in teeth treated with heparin averaged 82% of the defect height. Mean connective tissue repair in teeth treated with heparin and the implant was significantly greater and comprised approximately 99% of the defect height (P less than 0.05). Teeth treated with saline either with or without the implant also healed with almost complete connective tissue repair. The results support the importance of wound stabilization in periodontal wound healing. Development of biodegradable implant systems aimed at stabilizing and supporting the healing wound seems a desirable direction for future research in regenerative periodontal procedures.


New tricks from an old oncogene: gene fusion and copy number alterations of MYB in human cancer.
MYB is a leucine zipper transcription factor that is essential for hematopoesis and for renewal of colonic crypts. There is also ample evidence showing that MYB is leukemogenic in several animal species. However, it was not until recently that clear evidence was presented showing that MYB actually is an oncogene rearranged in human cancer. In a recent study, a novel mechanism of activation of MYB involving gene fusion was identified in carcinomas of the breast and head and neck. A t(6;9) translocation was shown to generate fusions between MYB and the transcription factor gene NFIB. The fusions consistently result in loss of the 3'-end of MYB, including several highly conserved target sites for microRNAs that negatively regulate MYB expression. Deletion of these target sites may disrupt the repression of MYB, leading to overexpression of MYB-NFIB transcripts and protein and to transcriptional activation of critical MYB target genes associated with apoptosis, cell cycle control, cell growth/angiogenesis and cell adhesion. This study, together with previous and recent data showing rearrangements and copy number alterations of the MYB locus in T-cell leukemia and certain solid tumors, will be the main focus of this review.


Safety profile of the quinolones.
The most important finding from preclinical evaluation of fluoroquinolones has been their arthropathogenic potential in young animals. This toxic effect is found with all quinolones known so far and has led to the decision not to use them in children and adolescents, despite the fact that the significance of the effect for humans is still unclear. The mutagenic potential of the drugs seems to be low although bacterial DNA-metabolism is a major target of their action. Newer in-vitro methods to study topoisomerases from bacterial and mammalian cells are suitable to detect differences in the derivatives with regard to their mutagenic potential. The major adverse effects observed clinically with the four most often used fluoroquinolones norfloxacin, ciprofloxacin, ofloxacin and enoxacin are gastrointestinal disturbances (1.8-5%), reactions of the central nervous system (0.9-1.6%) and skin reactions (0.6-1.4%). Higher incidences have been noticed during the clinical evaluation of fleroxacin at doses of 400 mg or more. A comparison of the adverse reaction frequencies of fluoroquinolones with those of other antimicrobial agents can most closely be made with the results from double-blind studies. Such results show that in most cases fluoroquinolones have been tolerated as well as or better than conventional drugs. Clinically relevant drug interactions have been observed with some quinolones that are metabolized primarily in the liver: enoxacin and ciprofloxacin reduce the theophylline clearance. Also, interactions of quinolones with Mg2(+)-containing antacids, which result in tremendous loss of bioavailability, are of therapeutic importance. Overall, fluoroquinolones are well tolerated and the incidences of side effects are similar to those of other antibacterials.


Prevalence of reported suicidal behaviour in the general population and mental health-care staff.
Higher rates of suicidal behaviour have been reported among staff in mental health care than in the general population. However, no studies of these two groups have been carried out simultaneously, using the same methods. This study aims to investigate whether they differ in terms of age- and sex-standardized prevalence of suicidal behaviour. Identical questions about suicidal behaviour were addressed in the same year to a random sample of the general population and to mental health-care staff in Stockholm. Life weariness among the latter was also investigated. Age- and sex-standardized past year prevalences of suicidal thoughts and suicide attempts were found to be similar among mental health-care staff and the general population. Lifetime prevalence of both suicidal thoughts and suicide attempts was significantly higher among mental health-care staff than among the general population. Psychologists/social workers have a higher probability of: lifetime thoughts of life is not worth living; death wishes; and, suicidal thoughts, than nurses/assistant nurses. Reports on lifetime prevalence of suicidal behaviour may be biased in populations that are not reminded of these problems in everyday life. Data on past year prevalence of suicidal behaviour show clearly the similarity between the general population and the mental health-care staff.


Does parent's psychological distress mediate the relationship between war trauma and psychosocial adjustment in children?
This study investigated the impact of war trauma on behavioral and emotional disorders, and neuroticism in children by prospectively examining the potential mediator and/or moderator effects of parental psychological distress. The sample consisted of 205 parents and their children. The results indicated that parent's psychological distress did mediate and moderate the effect of trauma exposure on emotional and behavioral disorders in children. An integrated intervention which simultaneously targets children and parental distress symptoms is needed. The integrated intervention may intend to use trauma-focused cognitive behavioral therapy model that integrates cognitive, behavioral, interpersonal, and family therapy principles with trauma interventions.


157 W all-fiber high-power picosecond laser.
An all-fiber high-power picosecond laser is constructed in a master oscillator power amplifier configuration. The self-constructed fiber laser seed is passively mode locked by a semiconductor saturable absorber mirror. Average output power of 157 W is obtained after three stages of amplification at a fundamental repetition rate of 60 MHz. A short length of ytterbium double-clad fiber with a high doping level is used to suppress nonlinear effects. However, a stimulated Raman scattering (SRS) effect occurs owing to the 78 kW high peak power. A self-made all-fiber repetition rate increasing system is used to octuple the repetition rate and decrease the high peak power. Average output power of 156.6 W is obtained without SRS under the same pump power at a 480 MHz repetition rate with 0.6 nm line width.


Natural-cause mortality and long-term exposure to particle components: an analysis of 19 European cohorts within the multi-center ESCAPE project.
Studies have shown associations between mortality and long-term exposure to particulate matter air pollution. Few cohort studies have estimated the effects of the elemental composition of particulate matter on mortality. Our aim was to study the association between natural-cause mortality and long-term exposure to elemental components of particulate matter. Mortality and confounder data from 19 European cohort studies were used. Residential exposure to eight a priori-selected components of particulate matter (PM) was characterized following a strictly standardized protocol. Annual average concentrations of copper, iron, potassium, nickel, sulfur, silicon, vanadium, and zinc within PM size fractions ≤ 2.5 μm (PM2.5) and ≤ 10 μm (PM10) were estimated using land-use regression models. Cohort-specific statistical analyses of the associations between mortality and air pollution were conducted using Cox proportional hazards models using a common protocol followed by meta-analysis. The total study population consisted of 291,816 participants, of whom 25,466 died from a natural cause during follow-up (average time of follow-up, 14.3 years). Hazard ratios were positive for almost all elements and statistically significant for PM2.5 sulfur (1.14; 95% CI: 1.06, 1.23 per 200 ng/m3). In a two-pollutant model, the association with PM2.5 sulfur was robust to adjustment for PM2.5 mass, whereas the association with PM2.5 mass was reduced. Long-term exposure to PM2.5 sulfur was associated with natural-cause mortality. This association was robust to adjustment for other pollutants and PM2.5.


Text Messages and Financial Incentives to Increase Physical Activity in Adolescents With Prediabetes and Type 2 Diabetes: Web-Based Group Interviews to Inform Intervention Design.
Physical activity is a major component of treatment for adolescents with obesity and prediabetes or type 2 diabetes; however, sedentary behavior remains pervasive. An SMS text message-based intervention paired with financial incentives may be an effective way to promote physical activity in this population. This study aims to obtain end-user feedback on SMS text message content and assess the acceptability of a planned SMS text messaging intervention with financial incentives to motivate youth with prediabetes or type 2 diabetes to increase physical activity. Adolescents with overweight or obesity and prediabetes or type 2 diabetes who attended a large academic pediatric endocrinology clinic were recruited to participate in group interviews (2-4/group) via videoconferencing. Participants were asked to share their thoughts on the use of SMS text messages and financial incentives to remind and motivate them to be more physically active. They rated and provided feedback on specific messages to be used in clinical trials. Participants were also asked about their personal experience with rewards to motivate behavior change and their anticipated reactions to rewards provided for goal attainment (gain-framing) versus those provided and then taken away if a goal was not met (loss-framing). The interviews were conducted by 2 trained interviewers and a note-taker. Content analysis was used to explore themes. Group interviews were completed with 20 participants (11/20, 55% women; 15/20, 75% with type 2 diabetes; 5/20, 25% with prediabetes) with a mean age of 15 (SD 1; range 12-18) years and a mean BMI of 41 (SD 5) kg/m2 (all >95th percentile for age and sex). Most participants were non-Hispanic Black (14/20, 70%) and 10% (2/20) were Hispanics. Participants frequently cited near-continuous smartphone use and agreed that SMS text messages would serve as good reminders to be physically active, but the consensus about the need for short messages was strong. Favorable content included references to what they were likely to be doing when messages were sent (eg, homework or watching television) and messages that were upbeat or informative. Specific physical activity suggestions were rated favorably. Attitudes toward financial incentives varied, with differing opinions about whether loss-framed incentives would be motivating or discouraging. Many participants highlighted the role of intrinsic, rather than extrinsic, motivation in achieving and sustaining behavior change. The engagement of adolescents with obesity and diabetes or prediabetes allowed for the refinement of SMS text messages for our planned intervention, with an emphasis on short, upbeat, relatable, and informative messages. Although an SMS text messaging intervention using financial incentives to motivate youth with prediabetes or type 2 diabetes to be more physically active is theoretically acceptable, the impact on actual activity levels in this population requires prospective evaluation in a clinical trial.


Characterization of variants of the pore-forming toxin ClyA from Escherichia coli controlled by a redox switch.
The α-pore-forming toxin Cytolysin A (ClyA) is responsible for the hemolytic phenotype of several Escherichia coli and Salmonella enterica strains. ClyA is a soluble, 34 kDa monomer that assembles into a dodecameric pore complex in the presence of membranes or detergent. The comparison of the X-ray structures of monomeric ClyA and the ClyA protomer in the pore complex revealed one of the largest conformational transitions observed so far in proteins, involving the structural rearrangement of more than half of all residues, which is consistent with the finding that conversion from the monomer to the assembly competent protomer is rate-limiting for pore assembly. Here, we introduced artificial disulfide bonds at two distinct sites into the ClyA monomer that both prevent a specific structural rearrangement required for protomer formation. Using electron microscopy and hemolytic activity assays, we show that the engineered disulfides indeed trap these ClyA variants in an assembly incompetent state. Assembly of the variants into functional pore complexes can be completely recovered by disulfide reduction. The assembly kinetics of the ClyA variants recorded with circular dichroism and fluorescence spectroscopy revealed the same mechanism of protomer formation that was observed for wild-type ClyA, proceeding via an intermediate with decreased secondary structure content.


What molecular assembly can learn from catalytic chemistry.
One important objective of molecular assembly research is to create highly complex functional chemical systems capable of responding, adapting, and evolving. Compared with living systems, the synthetic systems are still rather primitive and are far from realizing those features. Nature is by far the most important source of inspiration for designing and creating such systems. In this critical review, we summarize an alternative approach, inspired by catalysis, to examine and describe some molecular assembly processes. A new term, "catassembly," is suggested to refer to the increase in the rate and control of a molecular assembly process. This term combines the words "catalysis" and "assembly," and identifiably retains the Greek root "cat-" of catalysis. The corresponding verb is "catassemble" and the noun is "catassembler", referring to the "helper" species. Catassembly in molecular assembly is a concept that is analogous to catalysis in chemical synthesis. After using several examples to illustrate the characteristics of catassembly, we discuss future methodological and theoretical developments. We also emphasize the significance of the synergy between chemical synthesis and molecular assembly, especially for hierarchical assembly systems. Because most efforts in the field of molecular assembly have been devoted to the design and synthesis of molecular building blocks, we wish to stress the apparently missing yet critical link to complex chemical systems, i.e., the design and utilization of molecular catassemblers to facilitate the formation of functional molecular assemblies from building blocks with high efficiency and selectivity. This rational control and accelerated method will promote the systems chemistry approach, and may expand the spectrum of molecular assembly from basic science to applications.


Quality of life and pharmaco-economic aspects of obsessive-compulsive disorder. A South African survey.
The quality of life and pharmaco-economic aspects of obsessive-compulsive disorder (OCD) have received relatively little research attention to date. We aimed to gather preliminary data on these in a South African patient sample. A survey of members of the Obsessive-Compulsive Disorder Association of South Africa was undertaken by means of a detailed self-report questionnaire. Results of the survey suggest that OCD causes significant morbidity, leading to clear distress and Interference with academic, occupational, social and family function. Unfortunately, correct diagnosis and appropriate treatment have been delayed in many patients, and the financial costs of such incorrect management are likely to be considerable. Much further work needs to be done by the medical profession and by interested consumers to raise awareness about OCD and to provide information about its management. In South Africa, it is particularly Important to undertake such psycho-education at a primary health care level and to impact on patients of low socio-economic status.