Molecularly Tunable Fluorescent Quantum Defects.
We describe the chemical creation of molecularly tunable fluorescent quantum defects in semiconducting carbon nanotubes through covalently bonded surface functional groups that are themselves nonemitting. By variation of the surface functional groups, the same carbon nanotube crystal is chemically converted to create more than 30 distinct fluorescent nanostructures with unique near-infrared photoluminescence that is molecularly specific, systematically tunable, and significantly brighter than that of the parent semiconductor. This novel exciton-tailoring chemistry readily occurs in aqueous solution and creates functional defects on the sp(2) carbon lattice with highly predictable C-C bonding from virtually any iodine-containing hydrocarbon precursor. Our new ability to control nanostructure excitons through a single surface functional group opens up exciting possibilities for postsynthesis chemical engineering of carbon nanomaterials and suggests that the rational design and creation of a large variety of molecularly tunable quantum emitters-for applications ranging from in vivo bioimaging and chemical sensing to room-temperature single-photon sources-can now be anticipated.


Ginsenoside Rf alleviates dysmenorrhea and inflammation through the BDNF-TrkB-CREB pathway in a rat model of endometriosis.
To investigate the effects and the underlying mechanisms of ginsenoside Rf in a surgically induced rat endometriosis model, endometriosis was constructed through homologous transplantation and the Wistar rats were further randomly classified into the sham group, the estradiol valerate (E2V) control group, the endometriosis group, and the ginsenoside Rf groups (1.0, 2.0 and 4.0 mg kg-1, respectively). After 7 days of treatment, the implant volume and writhing responses were recorded. Vascular endothelial growth factor (VEGF), inducible nitric oxide synthase (iNOS), interleukin (IL)-6, IL-1β, and tumor necrosis factor (TNF)-α were analyzed using enzyme-linked immunosorbent assay (ELISA) and reverse transcription polymerase chain reaction (RT-PCR) assay. Brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinases (TrkB), and phosphate-c-AMP-responsive element binding protein (pCREB) were further measured. Compared with the endometriosis group, ginsenoside Rf could decrease the volume of the endometriotic implants and writhing responses. Furthermore, the expression levels of VEGF and inflammation-related iNOS, IL-6, IL-1β, and TNF-α were significantly down-regulated in the ginsenoside Rf groups in a dose-dependent manner. The results also showed that ginsenoside Rf could decrease the expression of BDNF, TrkB, and pCREB in the endometriotic implants. The alleviation of endometriosis-associated dysmenorrhea and inflammation by ginsenoside Rf may be partially mediated by the BDNF-TrkB-CREB pathway.


Energy landscape of domain motion in glutamate dehydrogenase deduced from cryo-electron microscopy.
Analysis of the conformational changes of protein is important to elucidate the mechanisms of protein motions correlating with their function. Here, we studied the spontaneous domain motion of unliganded glutamate dehydrogenase from Thermococcus profundus using cryo-electron microscopy and proposed a novel method to construct free-energy landscape of protein conformations. Each subunit of the homo-hexameric enzyme comprises nucleotide-binding domain (NAD domain) and hexamer-forming core domain. A large active-site cleft is situated between the two domains and varies from open to close according to the motion of a NAD domain. A three-dimensional map reconstructed from all cryo-electron microscopy images displayed disordered volumes of NAD domains, suggesting that NAD domains in the collected images adopted various conformations in domain motion. Focused classifications on NAD domain of subunits provided several maps of possible conformations in domain motion. To deduce what kinds of conformations appeared in EM images, we developed a novel analysis method that describe the EM maps as a linear combination of representative conformations appearing in a 200-ns molecular dynamics simulation as reference. The analysis enabled us to estimate the appearance frequencies of the representative conformations, which illustrated a free-energy landscape in domain motion. In the open/close domain motion, two free-energy basins hindered the direct transformation from open to closed state. Structure models constructed for representative EM maps in classifications demonstrated the correlation between the energy landscape and conformations in domain motion. Based on the results, the domain motion in glutamate dehydrogenase and the analysis method to visualize conformational changes and free-energy landscape were discussed. DATABASE: The EM maps of the four conformations were deposited to Electron Microscopy Data Bank (EMDB) as accession codes EMD-9845 (open), EMD-9846 (half-open1), EMD-9847 (half-open2), and EMD-9848 (closed), respectively. In addition, the structural models built for the four conformations were deposited to the Protein Data Bank (PDB) as accession codes 6JN9 (open), 6JNA (half-open1), 6JNC (half-open2), and 6JND (closed), respectively.


Association of urinary melatonin levels and aging-related outcomes in older men.
Circadian disruptions can contribute to accelerated aging, and the circadian system regulates cognitive and physical functions; therefore, circadian markers (eg, melatonin) may be associated with key aspects of healthy aging and longevity. To evaluate urinary melatonin levels in relation to cognitive function, physical function, and mortality among 2,821 older men in the Osteoporotic Fractures in Men Study DESIGN: Cohort study. In 2003-2005, participants provided first-morning spot urine samples, which were assayed for 6-sulfatoxymelatonin (the primary melatonin metabolite in urine); cognitive and physical function assessments were completed twice, at baseline and an average of 6.5 years later. Participant deaths were confirmed by central review of death certificates over a mean of 9.2 years of follow up. In multivariable-adjusted regression models, we observed a significant trend of better Digit Vigilance Test scores (ie, decreased time to completion) at baseline across increasing melatonin quartiles (p-trend = 0.01); however, mean time-to-completion scores did not significantly differ comparing extreme quartiles (group means: 547.1 seconds (95% CI: 533.6, 560.6) versus 561.3 seconds (95% CI: 547.8, 574.9)), and there were no associations of urinary melatonin levels with other cognitive test scores, or any cognitive change scores over time. Furthermore, melatonin levels were not related to physical function scores (p-trends = 0.4 for walking speed, 0.7 for chair stands, and 0.6 for grip strength in fully-adjusted models) or mortality risk (p-trend = 0.3 in the fully-adjusted model). We found little evidence of associations between urinary melatonin levels and key measures of healthy aging and mortality in this cohort of older men. Further research should explore the relation of melatonin, particularly if assessed earlier in life, and other circadian markers with healthy aging outcomes.


Expression of multiple apoptosis-regulatory genes in human breast cancer cell lines and primary tumors.
The expression of several apoptosis-regulating genes was evaluated in 9 human breast cancer cell lines, 2 immortalized human mammary epithelial lines, 1 normal breast tissue biopsy, and 3 primary breast tumors, using a multiple antigen detection (MAD) immunoblotting method. The anti-apoptotic proteins Bcl-2, Bcl-X(L), Mcl-1, and BAG-1 were present at immunodetectable levels in 7, 10, 10, and 9 of the 11 lines. Comparing these 11 cell lines among themselves revealed that steady-state levels of Bcl-2, Bcl-X(L), Mcl-1, and BAG-1 were present at relatively higher levels in 4, 6, 5, and 5 of the lines, respectively. In contrast, the pro-apoptotic proteins Bax and Bak were detected in all 11 cell lines, and were present at relatively higher levels in 10 and 5 of the 11 lines, respectively. The Interleukin-1beta converting enzyme (ICE) homolog CPP32 (Caspase-3) was expressed in 10/11 breast cell lines. High levels of p53 protein, indicative of mutant p53, were found in 8 of the 11 lines and correlated inversely with Bax expression (p = 0.01). Bcl-2 and BAG-1 protein levels were positively correlated (p = 0.03). Immunoblot analysis of primary adenocarcinomas revealed expression of the anti-apoptotic proteins Bcl-2, Bcl-X(L), Mcl-1, and BAG-1, as well as the pro-apoptotic proteins Bax, Bak, and CPP32, in at least 2 of the 3 tumors examined. Immunohistochemical analysis was also performed for all of these proteins using 20 paraffin-embedded breast cancer biopsy specimens that all contained residual normal mammary epithelium in combination with both invasive cancer and carcinoma in situ. All of these apoptosis-regulating proteins were detected in primary breast cancers, though the percentage of immunopositive tumor cells varied widely in some cases. Comparisons of the intensity of immunostaining in normal mammary epithelium and invasive carcinoma suggested that Bcl-2 immunointensity tends to be lower in cancers than normal breast epithelium (p = 0.03), whereas CPP32 immunointensity was generally higher in invasive cancers (p < 0.0001). Taken together, the results demonstrate expression of multiple apoptosis-modulating proteins in breast cancer cell lines and primary tumors, suggesting complexity in the regulation of apoptosis in these neoplasms of mammary epithelial origin.


Occurrence of carbapenem-resistant Acinetobacter baumannii clones at multiple hospitals in London and Southeast England.
From late 2003 to the end of 2005, the Health Protection Agency's national reference laboratories received approximately 1,600 referrals of Acinetobacter spp., including 419 and 58 examples, respectively, of two carbapenem-resistant Acinetobacter baumannii lineages, designated OXA-23 clones 1 and 2. Representatives of these clones were obtained from 40 and 8 hospitals, respectively, in London or elsewhere in Southeast England. Both clones had blaOXA-23-like genes, as well as the intrinsic (but downregulated) blaOXA-51-like carbapenemase genes typical of A. baumannii. Both were highly multiresistant: only colistin and tigecycline remained active versus OXA-23 clone 1 isolates; OXA-23 clone 2 isolates were also susceptible to amikacin and minocycline. These lineages increase the burden created by the southeast (SE) clone, a previously reported A. baumannii lineage with variable carbapenem resistance contingent on upregulation of the blaOXA-51-like gene. Known since 2000, the SE clone had been referred from over 40 hospitals by the end of 2005, with 627 representatives received by the reference laboratories. The OXA-23 clone 2 is now in decline, but OXA-23 clone 1 continues to be referred from new sites, as does the SE clone. Their spread is forcing the use of unorthodox therapies, principally colistin and tigecycline, although the optimal regimens remain uncertain.


Estimation of total body weight in obese patients.
Knowledge of accurate patient weight is vital to safe air medical transport and critical care. Patient weight is often unknown in emergency settings, and visual estimations have been shown to be inaccurate, especially in obese patients. We hypothesized that a simple formula based on anthropometric measurements could accurately predict patient weight for obese adult men and women. Data from cross-sectional anthropometric measurements from the National Health and Nutrition Examination Survey (NHANES) III (1988-1994)-height, leg length, thigh circumference, and mid-arm circumference-were used to estimate patient weight among adult (18 years and older) men and nonpregnant women who weighed at least 100 kg (N = 1,471). Linear modeling was used to develop simple sex-specific linear models to estimate patient weight. Models were derived on a random 67% subset of the original sample and then validated against the remaining 33% to assess the model's predictive capacity. The combination of arm circumference and height yielded the best model: Women: weight (WT) = -64.6 + 2.15 x arm circumference (ARM) + 0.54 x height (HT) (adjusted R(2): 0.55); men: WT = -93.2 + 3.29 x ARM + 0.43 x HT (adjusted R(2): 0.59). Approximately 90% of patient weights were accurately estimated within a 15% error tolerance. We have derived and validated simple equations with easy-to-use tables to accurately predict total body weight of obese men and women using only height and arm circumference. These tables may assist air medical transport pilots and medical crews make decisions about which patients may be safely transported, how far they may be transported, how much fuel is required, and how many crewmembers and family members may accompany them.


Motif inference reveals optimal CTL epitopes presented by HLA class I alleles highly prevalent in southern Africa.
HIV-specific CTL play a central role in immune control of HIV. The basis for understanding the success or failure of this immune response requires identification of the specific epitopes targeted by CTL. However, in populations most severely affected by the global epidemic, this fundamental knowledge is hindered by the lack of characterization of many of the HLA class I alleles highly prevalent in such populations. Overall, the peptide-binding motif has been determined for a small minority (9%) of HLA class I alleles, with a strong bias toward those alleles prevalent in Caucasoid populations. These studies therefore set out to define, in a South African Zulu/Xhosa population at the epicenter of the epidemic, the epitopes presented by alleles highly prevalent, but for which the peptide-binding motif had not been characterized. Using a method of motif inference, epitopes presented by four such alleles prevalent in the Zulu/Xhosa population of Durban, South Africa, namely, B*3910, B*4201, B*8101, and Cw*1801, are described. Importantly, this approach may additionally facilitate optimization of epitopes in certain instances where conflicting reports in the literature exist regarding the peptide-binding motif, such as for HLA-A*2902, also highly prevalent in southern African populations. These data indicate that the previously anomalous position of HLA-A*2902 among HLA-A alleles, outside any recognized HLA-A supertype, is artifactual, and the true position of the A*2902 motif overlaps those of the A1 and A24 supertypes.


'My position is, when it comes to the risk side, you've got to partner'.
Anthony Tersigni, the CEO of Ascension, oversees a sprawling empire of 141 Catholic hospitals in 24 states and the District of Columbia with 150,000 employees over 2,500 care sites. At a time of potentially far-reaching political changes, the $21 billion organization is going through its own transition, having recently tapped Chief Operating Officer Patricia Maryland to succeed Robert Henkel as CEO of Ascension Health, the holding company's largest operating division. During January's J.P. Morgan Healthcare Conference in San Francisco, Modern Healthcare finance reporter Dave Barkholz spoke with Tersigni about the drama in Washington over repealing and replacing the Affordable Care Act, what the nation's largest not-for-profit healthcare group has planned regarding mergers and acquisitions and the transition underway at Ascension. The following is an edited transcript.


gamma-Aminobutyric acidA receptors and spinally mediated antinociception in rats.
Experiments were performed on rats with lumbar subarachnoid catheters, using four agonist drugs [gamma-aminobutyric acid (GABA), muscimol, midazolam and 5-hydroxytryptamine (5-HT)] and two GABA(A) antagonists (bicuculline and SR-95531) given intrathecally. All four agonists caused dose-related antinociception assessed by the electrical current threshold test. These effects were spinally mediated because the agonists caused increases in nociceptive thresholds in the skin of the tail and not the neck. In the same experiments, 5-HT and GABA caused simultaneous increases in tail-flick latency and electrical current thresholds in the tail. Both GABA(A) antagonists caused dose-related suppression of the antinociceptive effects of equieffective doses of all four agonists. Tail-flick latency increases caused by 5-HT were not suppressed by bicuculline in the same experiments in which bicuculline had suppressed the electrical current threshold effects of intrathecal 5-HT. The log dose-response curves for both antagonists for suppression of GABA effects were coincident, having a very shallow slope and covering the whole range of doses effective against the other agonists. The two GABA(A) antagonists were very different in relative potency for suppression of the spinally mediated antinociceptive effects of the other three agonists. The rank order of potency for bicuculline suppression of the effects of equieffective doses of the other agonists was muscimol > 5-HT > midazolam, whereas the rank order for SR-95531 was muscimol >> midazolam > 5-HT. We conclude that there exist in the spinal cord at least three different GABA(A) receptors responsible for spinally mediated antinociception caused by intrathecal injections of midazolam, muscimol and 5-HT. These are all targets for endogenous GABA.


Changes in gene expression in the lungs of Mg-deficient mice are related to an inflammatory process.
It has been well documented that experimental hypomagnesemia in rodents evokes, as an early consequence, an inflammatory response. This also leads to the activation of cells producing reactive species of oxygen and, as a result, to the oxidative damage of tissues. Several studies have shown that lungs might be a specific target of Mg deficiency. Here, we report that 3 weeks of Mg deficiency in mice resulted in inflammatory processes in the lungs, including interstitial and perivascular pneumonia, manifested by the infiltration of leukocytes, plasmocytes and histiocytes, as well as the phenomenon of disseminated intravascular coagulation (DIC). These phenomena were accompanied by changes in gene expression assessed by cDNA array. In this study we identified 26 genes significantly changed by Mg deficiency, mostly involved in the anti-oxidative response, regulation of cell cycle and growth, apoptosis as well as cell-cell and cell-matrix interactions. We conclude that these changes are related to the phenomena of inflammatory and oxidative processes and consecutive remodeling occurring in the tissues as a result of Mg deficiency. This may have implications for at least several lung pathologies, including allergies, asthma, SIDS (Sudden Infant Death Syndrome) or facilitate formation of lung metastases.


Kainic acid-induced neurotrophic activities in developing cortical neurons.
Using primary cultured cortical neurons from embryonic rat brains, we elucidated an alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)/kainic acid (KA) receptor-mediated neuroprotective mechanism through actions of nerve growth factor (NGF) in developing neurons. Neurotoxicity of KA in early days in vitro neurons was quite low compared with the mature neurons. However, pretreatment with anti-NGF antibody or TrkA inhibitor AG-879 profoundly raised KA toxicity. Furthermore, KA stimulation resulted in an increase of TrkA expression and phosphorylation, which was blocked not only by the AMPA/KA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione and AG-879, but also by the phospholipase C inhibitor U73122 and the intracellular calcium chelator BAPTA. A study of polyphosphoinositide turnover showed that KA-stimulated phospholipase C (PLC) activity was directly triggered by the AMPA/KA receptor activity, but not by the activity of TrkA or other excitatory amino acid receptor subtypes. Sources of KA-increased intracellular calcium levels were contributed by both extracellular calcium influx and intracellular calcium release and were partially sensitive to guanosine 5'-O-(2-thiodiphosphate). These results indicate that in developing cortical neurons, activation of AMPA/KA receptors by KA may induce expression, followed by activation of TrkA via PLC signaling and intracellular calcium elevation and hence increase reception of NGF on KA-challenged neurons. A G protein-coupled AMPA/KA receptor may be involved in these metabotropic events for neuronal protection.


Percutaneous Coronary Intervention in A Rare Case of Single Coronary Ostium Presented with ST Elevation Myocardial Infarction.
Anomalous aortic origin of the left coronary artery (AAOLCA) from the right sinus of Valsalva is a very rare coronary anomaly that can lead to sudden cardiac death (SCD), usually during or after strenuous exercise. The anatomical variation can follow five different courses: interarterial, subpulmonic (intraconal or intraseptal), prepulmonic, retroaortic, or retrocardiac. The interarterial variation is the pattern that has a stronger relationship with SCD. In patients with AAOLCA, ST-segment elevation myocardial infarction (STEMI) is a rare clinical presentation, and the management of an anomalous infarct-related coronary artery may be technically challenging. We report a case of a patient with an AAOLCA who presented with inferior STEMI and who underwent a successful percutaneous coronary intervention of the right coronary artery.


Whole grain and body weight changes in apparently healthy adults: a systematic review and meta-analysis of randomized controlled studies.
Whole grains have received increased attention for their potential role in weight regulation. A high intake has been associated with smaller weight gain in prospective cohort studies, whereas the evidence from randomized controlled studies has been less consistent. We assessed the effects of whole-grain compared with non-whole-grain foods on changes in body weight, percentage of body fat, and waist circumference by using a meta-analytic approach. We conducted a systematic literature search in selected databases. Studies were included in the review if they were randomized controlled studies of whole-grain compared with a non-whole-grain control in adults. A total of 2516 articles were screened for eligibility, and relevant data were extracted from 26 studies. Weighted mean differences were calculated, and a metaregression analysis was performed by using the whole-grain dose (g/d). Data from 2060 participants were included. Whole-grain intake did not show any effect on body weight (weighted difference: 0.06 kg; 95% CI: -0.09, 0.20 kg; P = 0.45), but a small effect on the percentage of body fat was seen (weighted difference: -0.48%; 95% CI: -0.95%, -0.01%; P = 0.04) compared with that for a control. An examination of the impact of daily whole-grain intake could predict differences between groups, but there was no significant association (β = -0.0013 kg × g/d; 95% CI: -0.011, 0.009 kg × g/d). Whole-grain consumption does not decrease body weight compared with control consumption, but a small beneficial effect on body fat may be present. The relatively short duration of intervention studies (≤16 wk) may explain the lack of difference in body weight and fat. Discrepancies between studies may be caused by differences in study design.


Sex-specific gene and pathway modeling of inherited glioma risk.
To date, genome-wide association studies (GWAS) have identified 25 risk variants for glioma, explaining 30% of heritable risk. Most histologies occur with significantly higher incidence in males, and this difference is not explained by currently known risk factors. A previous GWAS identified sex-specific glioma risk variants, and this analysis aims to further elucidate risk variation by sex using gene- and pathway-based approaches. Results from the Glioma International Case-Control Study were used as a testing set, and results from 3 GWAS were combined via meta-analysis and used as a validation set. Using summary statistics for nominally significant autosomal SNPs (P < 0.01 in a previous meta-analysis) and nominally significant X-chromosome SNPs (P < 0.01), 3 algorithms (Pascal, BimBam, and GATES) were used to generate gene scores, and Pascal was used to generate pathway scores. Results were considered statistically significant in the discovery set when P < 3.3 × 10-6 and in the validation set when P < 0.001 in 2 of 3 algorithms. Twenty-five genes within 5 regions and 19 genes within 6 regions reached statistical significance in at least 2 of 3 algorithms in males and females, respectively. EGFR was significantly associated with all glioma and glioblastoma in males only and a female-specific association in TERT, all of which remained nominally significant after conditioning on known risk loci. There were nominal associations with the BioCarta telomeres pathway in both males and females. These results provide additional evidence that there may be differences by sex in genetic risk for glioma. Additional analyses may further elucidate the biological processes through which this risk is conferred.


Laryngeal response patterns influence the efficacy of mechanical assisted cough in amyotrophic lateral sclerosis.
Most patients with amyotrophic lateral sclerosis (ALS) are treated with mechanical insufflation-exsufflation (MI-E) in order to improve cough. This method often fails in ALS with bulbar involvement, allegedly due to upper-airway malfunction. We have studied this phenomenon in detail with laryngoscopy to unravel information that could lead to better treatment. We conducted a cross-sectional study of 20 patients with ALS and 20 healthy age-matched and sex-matched volunteers. We used video-recorded flexible transnasal fibre-optic laryngoscopy during MI-E undertaken according to a standardised protocol, applying pressures of ±20 to ±50 cm H2O. Laryngeal movements were assessed from video files. ALS type and characteristics of upper and lower motor neuron symptoms were determined. At the supraglottic level, all patients with ALS and bulbar symptoms (n=14) adducted their laryngeal structures during insufflation. At the glottic level, initial abduction followed by subsequent adduction was observed in all patients with ALS during insufflation and exsufflation. Hypopharyngeal constriction during exsufflation was observed in all subjects, most prominently in patients with ALS and bulbar symptoms. Healthy subjects and patients with ALS and no bulbar symptoms (n=6) coordinated their cough well during MI-E. Laryngoscopy during ongoing MI-E in patients with ALS and bulbar symptoms revealed laryngeal adduction especially during insufflation but also during exsufflation, thereby severely compromising the size of the laryngeal inlet in some patients. Individually customised settings can prevent this and thereby improve and extend the use of non-invasive MI-E.


Ichthyobodo necator (Kinetoplastida)--a complex of sibling species.
Ichthyobodo necator is a parasitic flagellate that attacks fishes, causing disease problems in freshwater worldwide. Findings of similar flagellates in strictly marine fishes have indicated that ichthyobodiosis may be caused by more than 1 flagellate species. We obtained partial small subunit rDNA (ssu rDNA) sequences of 14 Ichthyobodo isolates originating from fishes in Norway, Japan, Singapore, South Africa and Brazil, and identified 8 strains or species, including 2 species infecting cultured salmon in Norway. An Ichthyobodo species isolated from the skin of Atlantic salmon parr in freshwater is suggested to represent L. necator sensu stricto, while another species, showing particular affinity for the gills, infects salmon in both fresh- and seawater. Atlantic cod is infected with a marine Ichthyobodo species unrelated to those infecting salmonids; 2 cyprinids originating from different parts of the world had related Ichthyobodo strains/species, and 2 isolates from unrelated North and South American fishes were also closely related. The phylogenetic relationships of the Ichthyobodo isolates is described, and the implications of the molecular findings on past and future morphological studies of Ichthyobodo spp. are discussed.


IL-25 improves IgA levels during parenteral nutrition through the JAK-STAT pathway.
Parenteral nutrition (PN) impairs mucosal immunity and increases the risk of infection in part via lower IgA levels at mucosal surfaces. Transport of immunoglobulin A (IgA) across the mucosa to the gut lumen depends on the epithelial transport protein, polymeric immunoglobulin receptor (pIgR), which is reduced during PN. In vitro, studies demonstrate that IL-4 up-regulates pIgR production via Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling. Because IL-4 stimulates IgA and is reduced during PN, we hypothesized that the suppressed pIgR is a result of decreased JAK-1 and STAT-6 phosphorylation. Because IL-4 is mediated by IL-25, we also hypothesized that PN + IL-25 would restore luminal IgA by increasing phosphorylated JAK-1 and STAT-6, resulting in increased tissue pIgR and luminal IgA. Experiment 1: 2 days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 11) or PN (n = 9). Experiment 2: 2 days after intravenous cannulation, male Institute of Cancer Research mice were randomized to chow (n = 12), PN (n = 10), or PN + 0.7 μg of exogenous IL-25 (n = 11) per day. After 5 days, distal ileum tissue was collected, homogenized, and protein extracted for JAK-STAT expression levels using a phospho-specific antibody microarray. Tissue was homogenized to measure pIgR expression via Western blot or fixed in 4% paraformaldehyde to measure pIgR expression via immunohistochemistry. Small intestinal wash fluid was collected and IgA was quantified using enzyme-linked immunosorbent assay. Experiment 1: PN significantly reduced phosphorylated JAK-1 and STAT-6 compared with chow. PN also decreased the tissue levels of the Th2 cytokines, IL-4 and IL-13, as well as pIgR, and luminal IgA compared with chow. Experiment 2: Exogenous administration of PN + IL-25 increased the phosphorylated JAK-1 and STAT-6 compared with PN alone. IL-25 completely restored expression of IL-13 to chow levels. IL-4, pIgR, IgA, and phosphorylated JAK-1 were significantly increased with IL-25 treatment compared with PN but failed to reach levels measured in chow. STAT-6 was significantly increased with IL-25 treatment compared with chow and PN. PN significantly decreases the JAK-STAT pathway by reducing levels of phosphorylated STAT-6 and JAK-1. Consistent with our previous work, sIgA, pIgR, and IL-4 decreased with PN, whereas the addition of IL-25 to PN reversed these decreases and demonstrated the role of the JAK-STAT pathway in vivo during PN.


Organized simultaneous displays facilitate learning of complex natural science categories.
Subjects learned to classify images of rocks into the categories igneous, metamorphic, and sedimentary. In accord with the real-world structure of these categories, the to-be-classified rocks in the experiments had a dispersed similarity structure. Our central hypothesis was that learning of these complex categories would be improved through observational study of organized, simultaneous displays of the multiple rock tokens. In support of this hypothesis, a technique that included the presentation of the simultaneous displays during phases of the learning process yielded improved acquisition (Experiment 1) and generalization (Experiment 2) compared to methods that relied solely on sequential forms of study and testing. The technique appears to provide a good starting point for application of cognitive-psychology principles of effective category learning to the science classroom.


Mapping the brain pathways of declarative verbal memory: Evidence from white matter lesions in the living human brain.
Understanding the contribution of the brain white matter pathways to declarative verbal memory processes has been hindered by the lack of an adequate model in humans. An attractive and underexplored approach to study white matter region functionality in the living human brain is through the use of non-aprioristic models which specifically search disrupted white matter pathways. For this purpose, we employed voxel-based lesion-function mapping to correlate white matter lesions on the magnetic resonance images of 46 multiple sclerosis patients with their performance on declarative verbal memory storage and retrieval. White matter correlating with storage was in the temporal lobe-particularly lateral to the hippocampus and in the anterior temporal stem-, in the thalamic region and in the anterior limb of the internal capsule, all on the left hemisphere, and also in the right anterior temporal stem. The same volumes were relevant for retrieval, but to them were added temporo-parieto-frontal paramedian bundles, particularly the cingulum and the fronto-occipital fasciculus. These 3D maps indicate the white matter regions most critically involved in declarative verbal memory in humans.


Reducing onchocerciasis-associated morbidity in onchocerciasis-endemic foci with high ongoing transmission: a focus on the children.
Efforts are being directed toward the elimination of onchocerciasis transmission in endemic areas with community-directed treatment with ivermectin (CDTI) in Africa, which greatly reduces onchocerciasis-associated disease. However, onchocerciasis remains a major public health problem in areas of South Sudan, the Democratic Republic of the Congo, Cameroon, and the Central African Republic. Strengthening onchocerciasis elimination efforts in areas with a high prevalence of disease burden is crucial to decrease transmission, morbidity, and mortality. We argue that clinical trials are needed to investigate the safety and efficacy of ivermectin treatment of Onchocerca volvulus-infected pregnant women and children younger than 5 years. Crucially, 6-monthly administration of ivermectin in school-age children at risk of onchocerciasis-associated epilepsy could be achieved by supplementing annual CDTI with an extra round of ivermectin treatment during Child Health Days in schools and/or other distribution sites every year. These strategies would help achieve the elimination of onchocerciasis and its associated disease burden.


ADHD in adolescents with borderline personality disorder.
The aims of this study were to assess the prevalence of a comorbid Attention Deficit Hyperactivity Disorder (ADHD) diagnosis in Borderline Personality Disorder (BPD), and its impact on the clinical presentation of BPD in adolescents, and to determine which type of impulsivity specifically characterizes adolescents with BPD-ADHD. ADHD diagnoses were sought in a sample of 85 DSM-IV BPD adolescents drawn from the EURNET BPD. Axis-I and -II disorders were determined with the K-SADS-PL and the SIDP-IV, respectively. Impulsivity was assessed with the BIS-11. 11% (N = 9) of BPD participants had a current ADHD diagnosis. BPD-ADHD adolescents showed higher prevalence of Disruptive disorders (Chi2 = 9.09, p = 0.01) and a non-significant trend for a higher prevalence of other cluster B personality disorders (Chi2 = 2.70, p = 0.08). Regression analyses revealed a significant association between Attentional/Cognitive impulsivity scores and ADHD (Wald Z = 6.69; p = 0.01; Exp(B) = 2.02, CI 95% 1.19-3.45). Comorbid ADHD influences the clinical presentation of adolescents with BPD and is associated with higher rates of disruptive disorders, with a trend towards a greater likelihood of cluster B personality disorders and with higher levels of impulsivity, especially of the attentional/cognitive type. A subgroup of BPD patients may exhibit developmentally driven impairments of the inhibitory system persisting since childhood. Specific interventions should be recommended for this subsample of BPD adolescents.


Epidemiology of rapes in Costa Rica: characterization of victims, perpetrators and circumstances surrounding forced intercourse.
Since the year 2000, the number of rapes in Costa Rica has increased at a rate of 42 cases per year. In 2011, 1786 rape cases were reported to the prosecution offices throughout the country, but only 1081 reports continued through the investigation process by the Judicial Investigation Agency. A randomly collected sample of 272 reports received by Judicial Investigation Agency, between July 2012 and June 2013, were prospectively studied. The analysis was limited to cases reported within 30 days following the rape. Results indicate that most of the provinces in the country show an incidence of about 38 cases/100,000 inhabitants. Ninety-six percent of the victims were women, 50% of which were between 10 and 19 years old. More than 99.5% of violators were men. The rape was perpetrated by a single aggressor in 85% of the cases. It was found that 48% of the victims were within the first 11 days of their menstrual cycle at the time of the attack. Twenty-nine percent of rapes occurred in "high rape-risk" circumstances--e.g., victims attacked by strangers in public outdoors or indoors. Twenty-five percent of rapes occur in "moderate rape-risk" circumstances--e.g., victims attacked indoors at public locations or at the home other than the victim's by relatives, sentimental partners or acquaintances. Fifteen percent of rapes occurred in "low rape-risk" circumstances--e.g., victims attacked in their homes by relatives or sentimental partners. In 67% of the cases the perpetrator was an acquaintance of the victim. Eleven percent of the cases corresponded to rapes in which the perpetrator was a partner or ex-partner of the victim. Fourteen percent and 25% of rapes could be classified as "proactive drug-facilitated rapes" or "opportunistic drug-facilitated rapes", respectively. Semen in the vaginal fluid of victims and the genetic profile of the alleged perpetrator were detected in 55% and 33% of the cases, respectively.


The loss of carbon dioxide from activated perbenzoate anions in the gas phase: unimolecular rearrangement via epoxidation of the benzene ring.
The unimolecular reactivities of a range of perbenzoate anions (X-C6H5CO3-), including the perbenzoate anion itself (X = H), nitroperbenzoates (X = para-, meta-, ortho-NO2), and methoxyperbenzoates (X = para-, meta-OCH3) were investigated in the gas phase by electrospray ionization tandem mass spectrometry. The collision-induced dissociation mass spectra of these compounds reveal product ions consistent with a major loss of carbon dioxide requiring unimolecular rearrangement of the perbenzoate anion prior to fragmentation. Isotopic labeling of the perbenzoate anion supports rearrangement via an initial nucleophilic aromatic substitution at the ortho carbon of the benzene ring, while data from substituted perbenzoates indicate that nucleophilic attack at the ipso carbon can be induced in the presence of electron-withdrawing moieties at the ortho and para positions. Electronic structure calculations carried out at the B3LYP/6-311++G(d,p) level of theory reveal two competing reaction pathways for decarboxylation of perbenzoate anions via initial nucleophilic substitution at the ortho and ipso positions, respectively. Somewhat surprisingly, however, the computational data indicate that the reaction proceeds in both instances via epoxidation of the benzene ring with decarboxylation resulting--at least initially--in the formation of oxepin or benzene oxide anions rather than the energetically favored phenoxide anion. As such, this novel rearrangement of perbenzoate anions provides an intriguing new pathway for epoxidation of the usually inert benzene ring.


Comparison of two Bayesian methods to detect mode effects between paper-based and computerized adaptive assessments: a preliminary Monte Carlo study.
Computerized adaptive testing (CAT) is being applied to health outcome measures developed as paper-and-pencil (P&P) instruments. Differences in how respondents answer items administered by CAT vs. P&P can increase error in CAT-estimated measures if not identified and corrected. Two methods for detecting item-level mode effects are proposed using Bayesian estimation of posterior distributions of item parameters: (1) a modified robust Z (RZ) test, and (2) 95% credible intervals (CrI) for the CAT-P&P difference in item difficulty. A simulation study was conducted under the following conditions: (1) data-generating model (one- vs. two-parameter IRT model); (2) moderate vs. large DIF sizes; (3) percentage of DIF items (10% vs. 30%), and (4) mean difference in θ estimates across modes of 0 vs. 1 logits. This resulted in a total of 16 conditions with 10 generated datasets per condition. Both methods evidenced good to excellent false positive control, with RZ providing better control of false positives and with slightly higher power for CrI, irrespective of measurement model. False positives increased when items were very easy to endorse and when there with mode differences in mean trait level. True positives were predicted by CAT item usage, absolute item difficulty and item discrimination. RZ outperformed CrI, due to better control of false positive DIF. Whereas false positives were well controlled, particularly for RZ, power to detect DIF was suboptimal. Research is needed to examine the robustness of these methods under varying prior assumptions concerning the distribution of item and person parameters and when data fail to conform to prior assumptions. False identification of DIF when items were very easy to endorse is a problem warranting additional investigation.


Common parietal activation in musical mental transformations across pitch and time.
We previously observed that mental manipulation of the pitch level or temporal organization of melodies results in functional activation in the human intraparietal sulcus (IPS), a region also associated with visuospatial transformation and numerical calculation. Two outstanding questions about these musical transformations are whether pitch and time depend on separate or common processing in IPS, and whether IPS recruitment in melodic tasks varies depending upon the degree of transformation required (as it does in mental rotation). In the present study we sought to answer these questions by applying functional magnetic resonance imaging while musicians performed closely matched mental transposition (pitch transformation) and melody reversal (temporal transformation) tasks. A voxel-wise conjunction analysis showed that in individual subjects, both tasks activated overlapping regions in bilateral IPS, suggesting that a common neural substrate subserves both types of mental transformation. Varying the magnitude of mental pitch transposition resulted in variation of IPS BOLD signal in correlation with the musical key-distance of the transposition, but not with the pitch distance, indicating that the cognitive metric relevant for this type of operation is an abstract one, well described by music-theoretic concepts. These findings support a general role for the IPS in systematically transforming auditory stimulus representations in a nonspatial context.


Urinary Metabolomics Study on the Protective Role of Cocoa in Zucker Diabetic Rats via 1H-NMR-Based Approach.
Cocoa constitutes one of the richest sources of dietary flavonoids with demonstrated anti-diabetic potential. However, the metabolic impact of cocoa intake in a diabetic context remains unexplored. In this study, metabolomics tools have been used to investigate the potential metabolic changes induced by cocoa in type 2 diabetes (T2D). To this end, male Zucker diabetic fatty rats were fed on standard (ZDF) or 10% cocoa-rich diet (ZDF-C) from week 10 to 20 of life. Cocoa supplementation clearly decreased serum glucose levels, improved glucose metabolism and produced significant changes in the urine metabolome of ZDF animals. Fourteen differential urinary metabolites were identified, with eight of them significantly modified by cocoa. An analysis of pathways revealed that butanoate metabolism and the synthesis and degradation of branched-chain amino acids and ketone bodies are involved in the beneficial impact of cocoa on diabetes. Moreover, correlation analysis indicated major associations between some of these urine metabolites (mainly valine, leucine, and isoleucine) and body weight, glycemia, insulin sensitivity, and glycated hemoglobin levels. Overall, this untargeted metabolomics approach provides a clear metabolic fingerprint associated to chronic cocoa intake that can be used as a marker for the improvement of glucose homeostasis in a diabetic context.


Clonal population of flucytosine-resistant Candida tropicalis from blood cultures, Paris, France.
Candida tropicalis is a diploid ascomycetes yeast responsible for 4%-24% of candidemia. Resistance to flucytosine is rarely described for this species but was observed for 45 (35%) of 130 C. tropicalis isolates recovered from blood cultures in the Paris area in a 4-year survey. The aims of this study were to test the hypothesis that the flucytosine-resistant isolates could represent a subgroup and to determine the relationship between epidemiologic and genomic data. Epidemiologic data and gene sequences were analyzed, and molecular typing was performed. Our results suggest that a clone of flucytosine-resistant isolates, associated with malignancies and a lower mortality than that for other C. tropicalis isolates, is widespread in the Paris area. We propose the analysis of 2 polymorphic microsatellite markers coupled with URA3 sequencing to track the clone.


Cis elements of the villin gene control expression in restricted domains of the vertical (crypt) and horizontal (duodenum, cecum) axes of the intestine.
Villin, an actin bundling protein found in the apical brush border of absorptive tissues, is one of the first structural genes to be transcriptionally activated in the embryonic intestinal endoderm. In the adult, villin is broadly expressed in every cell of the intestinal epithelium on both the vertical axis (crypt to villus tip) and the horizontal axis (duodenum through colon) of the intestine. Here, we document that a 12.4-kilobase region of the mouse villin gene drives high level expression of two different reporter genes (LacZ and Cre recombinase) within the entire intestinal epithelium of transgenic mice. Deletion of a portion of this transgene results in reduction of beta-galactosidase activity in restricted domains of the small intestine (duodenum) and large intestine (cecum). In addition, expression is reduced in the crypt compartment throughout the intestine. Thus, the global expression pattern of villin in the intestine is apparently the consequence of an amalgam of distinct and individual domain-specific control processes. That is, expression of villin in the duodenum and cecum requires different regulatory sequences than the rest of the intestine, and the expression of villin in crypts is regulated by different circuitry than expression of villin on villus tips.


Up close and personal: medical students prefer face-to-face teaching in psychiatry.
The aim of this paper was to determine the teaching activities most valued by medical students in the psychiatry rotation and to examine whether this varies with age, gender or stage of training. Medical students at Sydney Medical School were surveyed following an 8-week clinical attachment in psychiatry. Differences in ratings between activities were examined by means of ANOVA and post hoc contrasts. The learning activities involving face-to-face teaching received the highest ratings. The most valued tutorial was that given weekly by a dedicated academic clinician. No differences were seen with respect to age and gender. Inconsistent differences were seen between stages of training for skills sessions, but no other learning activities. Face-to-face clinical teaching should be a priority in clinical attachments in psychiatry as it is highly valued by students and contributes to positive attitudes towards psychiatry.


Comparison of the relative levels of the 3243 (A-->G) mtDNA mutation in heteroplasmic adult and fetal tissues.
In this report, levels of the 3243 A to G mtDNA mutation associated with the mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome were measured in different heteroplasmic tissues of subjects in a kindred including adults with variable clinical phenotypes and a fetus. The relative proportions of mutant mtDNA varied widely (0.03 to 0.67) between identical tissues of the six different subjects and between different tissues of the same subjects. In the one adult for whom sufficient data were available there was an apparent correlation between the distribution of mutant mtDNA and clinical presentation. A woman without neurological symptoms who died prematurely with a cardiomyopathy and lactic acidosis had higher proportions of mutant in heart (0.49, SD 0.02), skeletal muscle (0.56, SD 0.01), and liver (0.55, SD 0.12) than in other tissues studied (for example, kidney, 0.03, SD 0.01). A strikingly different result was found in a 24 week old fetus in whom there was little variation in heteroplasmy in different tissues (average proportion of mutant mtDNA in six tissues, 0.53, SD 0.02). These observations add cardiomyopathy to the growing list of presenting features of the 3243 mtDNA mutation. The unique results from the fetus suggest also that selection pressures acting on either wild type or 3243 mutant mtDNA (rather than variation from replicative segregation of the heteroplasmic mtDNA) may be responsible primarily for the variable levels of 3243 mutant mtDNA in different heteroplasmic tissues of adults.


Neurexin-1 and frontal lobe white matter: an overlapping intermediate phenotype for schizophrenia and autism spectrum disorders.
Structural variation in the neurexin-1 (NRXN1) gene increases risk for both autism spectrum disorders (ASD) and schizophrenia. However, the manner in which NRXN1 gene variation may be related to brain morphology to confer risk for ASD or schizophrenia is unknown. 53 healthy individuals between 18-59 years of age were genotyped at 11 single nucleotide polymorphisms of the NRXN1 gene. All subjects received structural MRI scans, which were processed to determine cortical gray and white matter lobar volumes, and volumes of striatal and thalamic structures. Each subject's sensorimotor function was also assessed. The general linear model was used to calculate the influence of genetic variation on neural and cognitive phenotypes. Finally, in silico analysis was conducted to assess potential functional relevance of any polymorphisms associated with brain measures. A polymorphism located in the 3' untranslated region of NRXN1 significantly influenced white matter volumes in whole brain and frontal lobes after correcting for total brain volume, age and multiple comparisons. Follow-up in silico analysis revealed that this SNP is a putative microRNA binding site that may be of functional significance in regulating NRXN1 expression. This variant also influenced sensorimotor performance, a neurocognitive function impaired in both ASD and schizophrenia. Our findings demonstrate that the NRXN1 gene, a vulnerability gene for SCZ and ASD, influences brain structure and cognitive function susceptible in both disorders. In conjunction with our in silico results, our findings provide evidence for a neural and cognitive susceptibility mechanism by which the NRXN1 gene confers risk for both schizophrenia and ASD.


Treatment patterns and burden of behavioral disturbances in patients with dementia in the United States: a claims database analysis.
Although patients with dementia frequently experience neuropsychological symptoms (NPS) such as agitation, which profoundly impacts patients, caregivers, and the healthcare system, few studies have evaluated the associated burden of agitation or agitation-related symptoms in dementia. This retrospective analysis of claims data from the Truven Health MarketScan® database (2012-2015) compared clinical characteristics, treatment patterns, healthcare resource utilization, and costs among patients with dementia with behavioral disturbances (BD) versus patients with dementia without BD. Existing BD diagnosis codes 294.11 or 294.21 were used as a means to identify patients with agitation/agitation-related symptoms. From a starting sample of 6.4 million beneficiaries, 103,402 patients with dementia were identified, of whom 16,440 (16%) had BD during an average of 17 months of follow-up. Patients with BD had significantly more medical and psychiatric comorbidities and greater comedication use (i.e., antidementia drugs, antidepressants, and antipsychotics; all values, P < .0001) compared with patients without BD. A significantly greater number of hospitalizations, hospital days, outpatient hospital/clinic visits, number of skilled nursing visits, and number of patients with hospice visit were reported during follow-up in patients with BD compared with patients without BD (all values, P < 0.0001). Costs were also significantly higher among patients with BD versus those patients without BD ($42,284 vs. $32,640, respectively; P < 0.0001). Patients with dementia with BD had a higher prevalence of comorbidities, greater use of comedications, and greater healthcare utilization and costs than patients with dementia without BD.


Flow-diameter phase shift. A potential indicator of conduit artery function.
This study assesses (1) the relation of the very-low-frequency vasomotion (< 0.02 Hz) of the radial artery of young healthy volunteers to regional blood flow and (2) its distribution in the upper extremities. Radial artery diameters from comparable sites were measured on contralateral extremities in 18 young healthy volunteers by an echo tracking system simultaneously with blood flow velocity determined by continuous wave Doppler and blood pressure acquired by photoplethysmography in the middle finger. A synchronous global pattern of vasomotion was detected on contralateral radial arteries, suggesting the presence of either a centrally located pacemaker or a humoral system. Modulation of sympathovagal balance in 8 subjects did not significantly alter either the frequency or amplitude of the very-low-frequency vasomotor waves. Matching patterns of diameter and flow oscillations of the very-low-frequency type recorded at the same site were obtained in 10 strictly nonsmoking volunteers for given periods of time. A consistent phase lag was observed between flow and diameter signals. Flow always preceded the diameter fluctuations by a mean (+/- SEM) course of 20.8 +/- 1.56 seconds. Although the physiological basis for oscillatory behavior remains for the moment highly speculative, these results suggest that the very-low-frequency vasomotion pattern in this conduit vessel might be a flow- or shear stress-dependent phenomenon. Shear stress changes at the endothelium modulate vascular tone through the release of vasodilators. The noninvasive assessment of the diameter-flow relation may thus offer a new way of addressing vascular wall function in medium-sized and large arteries in subjects with cardiovascular risk factors.


Target for standard Thai PCR assay identical in 12 white spot syndrome virus (WSSV) types that differ in DNA multiple repeat length.
A Thai PCR detection method (WSSV-232) yielding a 232 bp amplicon has been used for detection of white spot syndrome virus (WSSV) since 1996. It targets ORF 91 in the full sequence of the only Thai WSSV isolate at GenBank (AF369029). At the beginning of 2002, some Thai shrimp farmers complained that ponds stocked with WSSV-232 PCR negative post-larvae (PL) later suffered WSSV disease outbreaks. Although these outbreaks may have resulted from horizontal transmission of WSSV after stocking, it was also possible that they resulted from false negative PCR test results due to genetic changes at the PCR-assay target after the first appearance of WSSV in Thailand in 1995. Indeed, recent results have revealed at least 12 WSSV variants in Thailand that can be distinguished based on differences in DNA multiple repeat lengths in ORF 94 (GenBank AF369029). To test for variation in the WSSV-232 target sequence in ORF 91, 20 DNA extracts derived from field samples and representing 9 of the WSSV DNA multiple repeat groups were subjected to PCR amplification and sequencing using primers that generated a 403 bp amplicon covering the target for the WSSV-232 assay. An additional three repeat types were included from archived material. Analysis revealed that the 232 bp target sequence in ORF 91 was unchanged in all of the 12 types tested and that the original WSSV-232 detection system was still valid. Thus, any false negative PCR test results leading to farmer complaints would probably have arisen from small sample sizes and low sensitivity of the single-step PCR assay. If so, false negative results could be reduced by the use of nested PCR assays with larger PL sample sizes. .


Pd(ii)-Catalyzed gamma-C(sp3)-H alkynylation of amides: selective functionalization of R chains of amides R1C(O)NHR.
The gamma C(sp3)-H bond alkynylation of R chains of amides R1C(O)NHR, a fundamental class of synthetic substrates, has not been accomplished to date. Here, the first example of palladium(ii)-catalyzed alkynylation of an unactivated gamma C(sp3)-H bond of alkyl amides (cyclic, linear, and amino acids) is reported. The kinetic experiment shows that the rate of the reaction depends on the coupling partners and the amides. Late-stage diversification of alkynylated amides was developed by utilizing amine and alkyne functionalities.


Adherence to cancer prevention guidelines in 18 African countries.
Cancer rates in Africa are projected to double by 2030 due to aging and increased exposure to cancer risk factors, including modifiable risk factors. We assessed adherence to 5 modifiable cancer risk factors across 18 African countries. Data on adults 18 years and older were obtained from the 2002-2004 World Health Survey. Adherence to current World Cancer Research Fund guidelines on smoking, alcohol, body weight, physical activity, and nutrition was assessed. Adherence scores ranged from 0 (no guideline met) to 5 (all guidelines met). Determinants of adherence were assessed using multivariable linear regression adjusted for individual and country level characteristics. Across all countries, adherence to the guidelines among adults was high for smoking (72%-99%) and alcohol (85%-100%), but low for body weight (1.8%-78%), physical activity (3.4%-84%) and nutrition (1.4%-61%). Overall adherence score ranged from 2.32 in Mali to 3.72 in Comoros. In multivariable models, residing in low versus high SES households was associated with reduced adherence by 0.24 and 0.21 points for men and women respectively after adjusting for age, gender, education, and marital status (p<0.001). Every % increase in GDP spent on health was associated with increased adherence by 0.03 in men and 0.09 in women (p<0.001). The wide variation in adherence to cancer prevention guidelines observed across countries and between population sub-groups suggests the need for targeted public health efforts to improve behaviors related to body weight, physical activity and nutrition.


The Text-mining based PubChem Bioassay neighboring analysis.
In recent years, the number of High Throughput Screening (HTS) assays deposited in PubChem has grown quickly. As a result, the volume of both the structured information (i.e. molecular structure, bioactivities) and the unstructured information (such as descriptions of bioassay experiments), has been increasing exponentially. As a result, it has become even more demanding and challenging to efficiently assemble the bioactivity data by mining the huge amount of information to identify and interpret the relationships among the diversified bioassay experiments. In this work, we propose a text-mining based approach for bioassay neighboring analysis from the unstructured text descriptions contained in the PubChem BioAssay database. The neighboring analysis is achieved by evaluating the cosine scores of each bioassay pair and fraction of overlaps among the human-curated neighbors. Our results from the cosine score distribution analysis and assay neighbor clustering analysis on all PubChem bioassays suggest that strong correlations among the bioassays can be identified from their conceptual relevance. A comparison with other existing assay neighboring methods suggests that the text-mining based bioassay neighboring approach provides meaningful linkages among the PubChem bioassays, and complements the existing methods by identifying additional relationships among the bioassay entries. The text-mining based bioassay neighboring analysis is efficient for correlating bioassays and studying different aspects of a biological process, which are otherwise difficult to achieve by existing neighboring procedures due to the lack of specific annotations and structured information. It is suggested that the text-mining based bioassay neighboring analysis can be used as a standalone or as a complementary tool for the PubChem bioassay neighboring process to enable efficient integration of assay results and generate hypotheses for the discovery of bioactivities of the tested reagents.


Identification of the phenolic compounds contributing to antibacterial activity in ethanol extracts of Brazilian red propolis.
The purpose of this study is to identify the quantity and antibacterial activity of the individual phenolic compounds in Brazilian red propolis. Quantitative analysis of the 12 phenolic compounds in Brazilian red propolis was carried out using reversed-phase high-performance liquid chromatography. The main phenolic compounds in Brazilian red propolis were found to be (3S)-vestitol (1), (3S)-neovestitol (2) and (6aS,11aS)-medicarpin (4) with quantities of 72.9, 66.9 and 30.8 mg g of ethanol extracts(- 1), respectively. Moreover, the antibacterial activities of each compound against Staphylococcus aureus, Bacillus subtilis and Pseudomonas aeruginosa were evaluated by measuring the minimum inhibitory concentrations. In particular, compound 4 exhibited the most potent antibacterial activity among all the assayed compounds against selected bacteria, indicating that 4 is the most active compound in Brazilian red propolis extracts. Thus, Brazilian red propolis may be used as food additives and pharmaceuticals to protect against bacteria.


Kinetics and oxidative mechanism for H2O2-enhanced iron-mediated aeration (IMA) treatment of recalcitrant organic compounds in mature landfill leachate.
A hydrogen peroxide (H(2)O(2))-enhanced iron (Fe(0))-mediated aeration (IMA) process has been recently demonstrated to effectively remove organic wastes from mature landfill leachate. In this paper, the kinetics and oxidative mechanisms of the enhanced IMA treatment were studied. Bench-scale full factorial tests were conducted in an orbital shaker reactor for treatment of a mature leachate with an initial chemical oxygen demand (COD) of 900-1200 mg/L. At the maximum aeration rate (8.3 mL air/min mL sample), process variables significantly influencing the rates of H(2)O(2) decay and COD removal were pH (3.0-8.0), initial H(2)O(2) doses (0.21-0.84 M), and Fe(0) surface area concentrations (0.06-0.30 m(2)/L). Empirical kinetic models were developed and verified for the degradation of H(2)O(2) and COD. High DO maintained by a high aeration rate slowed the H(2)O(2) self-decomposition, accelerated Fe(0) consumption, and enhanced the COD removal. In hydroxyl radical (OH*) scavenging tests, the rate of removal of glyoxylic acid (target compound) was not inhibited by the addition of para-chlorobenzoic acid (OH* scavenger) at pH 7.0-7.5, ruling out hydroxyl radical as the principal oxidant in neutral-weakly basic solution. These experimental results show that this enhanced IMA technology is a potential alternative for the treatment of high strength recalcitrant organic wastewaters.


Scrub typhus in Southern India: are we doing enough?
Scrub typhus is a potentially fatal infectious disease caused by Orientia tsutsugamushi. We report on a retrospective analysis of clinical manifestations, lab investigations and outcome of patients admitted to our hospital from January 2009 to December 2009 with scrub typhus. The Weil-Felix test was the serological method used to diagnose scrub typhus. A total of 29 patients were diagnosed with scrub typhus and the majority of them presented with fever (100%), headache (51%), myalgia (51%) and gastrointestinal symptoms (44%) as predominant features. Six patients (20%) presented with altered sensorium and signs of meningial irritation. There is an emergence of rickettsial infection in southern India, posing diagnostic difficulty and delay in treatment. Early diagnosis and treatment are important as it prevents serious complications associated with the disease.


De novo prediction of PTBP1 binding and splicing targets reveals unexpected features of its RNA recognition and function.
The splicing regulator Polypyrimidine Tract Binding Protein (PTBP1) has four RNA binding domains that each binds a short pyrimidine element, allowing recognition of diverse pyrimidine-rich sequences. This variation makes it difficult to evaluate PTBP1 binding to particular sites based on sequence alone and thus to identify target RNAs. Conversely, transcriptome-wide binding assays such as CLIP identify many in vivo targets, but do not provide a quantitative assessment of binding and are informative only for the cells where the analysis is performed. A general method of predicting PTBP1 binding and possible targets in any cell type is needed. We developed computational models that predict the binding and splicing targets of PTBP1. A Hidden Markov Model (HMM), trained on CLIP-seq data, was used to score probable PTBP1 binding sites. Scores from this model are highly correlated (ρ = -0.9) with experimentally determined dissociation constants. Notably, we find that the protein is not strictly pyrimidine specific, as interspersed Guanosine residues are well tolerated within PTBP1 binding sites. This model identifies many previously unrecognized PTBP1 binding sites, and can score PTBP1 binding across the transcriptome in the absence of CLIP data. Using this model to examine the placement of PTBP1 binding sites in controlling splicing, we trained a multinomial logistic model on sets of PTBP1 regulated and unregulated exons. Applying this model to rank exons across the mouse transcriptome identifies known PTBP1 targets and many new exons that were confirmed as PTBP1-repressed by RT-PCR and RNA-seq after PTBP1 depletion. We find that PTBP1 dependent exons are diverse in structure and do not all fit previous descriptions of the placement of PTBP1 binding sites. Our study uncovers new features of RNA recognition and splicing regulation by PTBP1. This approach can be applied to other multi-RRM domain proteins to assess binding site degeneracy and multifactorial splicing regulation.


Can High-flow Nasal Cannula Reduce the Rate of Endotracheal Intubation in Adult Patients With Acute Respiratory Failure Compared With Conventional Oxygen Therapy and Noninvasive Positive Pressure Ventilation?: A Systematic Review and Meta-analysis.
The effects of high-flow nasal cannula (HFNC) on adult patients with acute respiratory failure (ARF) are controversial. We aimed to further determine the effectiveness of HFNC in reducing the rate of endotracheal intubation in adult patients with ARF by comparison to noninvasive positive pressure ventilation (NIPPV) and conventional oxygen therapy (COT). The PubMed, Embase, Medline, and the Cochrane Central Register of Controlled Trials databases, as well as the Information Sciences Institute Web of Science, were searched for all controlled studies that compared HFNC with NIPPV and COT in adult patients with ARF. The primary outcome was the rate of endotracheal intubation; the secondary outcomes were ICU mortality and length of ICU stay. Eighteen trials with a total of 3,881 patients were pooled in our final studies. Except for ICU mortality (I2 = 67%, χ2 = 12.21, P = .02) and rate of endotracheal intubation (I2 = 63%, χ2 = 13.51, P = .02) between HFNC and NIPPV, no significant heterogeneity was found in outcome measures. Compared with COT, HFNC was associated with a lower rate of endotracheal intubation (z = 2.55, P = .01) while no significant difference was found in the comparison with NIPPV (z = 1.40, P = .16). As for ICU mortality and length of ICU stay, HFNC did not exhibit any advantage over either COT or NIPPV. In patients with ARF, HFNC is a more reliable alternative than NIPPV to reduce the rate of endotracheal intubation than COT.


Single nucleotide polymorphisms of matrix metalloproteinase 9 (MMP9) and tumor protein 73 (TP73) interact with Epstein-Barr virus in chronic lymphocytic leukemia: results from the European case-control study EpiLymph.
Using EpiLymph case-control data, we found that chronic lymphocytic leukemia patients were more likely to have abnormal reactive serological patterns to Epstein Barr virus than controls. Here, we aimed to assess whether this association is modified by genetic variants. We examined 1,305 Single Nucleotide Polymorphisms from 300 selected genes related to various pathways in 240 cases and 513 controls from five European centers. In a recessive model, patients positive to aberrant antibody pattern and homozygous for rare genotypes in rs8113877T>G or rs17576A>G of the MMP9 gene were at highest risk of chronic lymphocytic leukemia. In a dominant model, TP73 showed the highest risk in patients positive to aberrant antibody pattern and homozygous for the wild-type genotype in rs1885859G>C or rs3765701A>T. All interactions were additive and no main effect was observed. The strong interactions observed may be indicative of a specific pathway in cancer genesis. Confirmation of these results is warranted.


Efficacy and safety of liraglutide monotherapy compared with metformin in Japanese overweight/obese patients with type 2 diabetes.
There is little information on direct comparison between metformin and glucagon-like peptide-1 (GLP-1) receptor agonists in the Asian population. This study examined the efficacy and safety of liraglutide monotherapy compared with metformin monotherapy in overweight/obese Japanese patients with type 2 diabetes (T2DM). The study was a 24-week, open-labeled, randomized controlled study. Overweight or obese patients with T2DM aged 20-75 years with suboptimal glycemic control were randomized to liraglutide or metformin monotherapy. The primary endpoint was change in HbA1c at week 24. Secondary endpoints included changes in daily glycemic profile, body weight, incidence of hypoglycemia and other adverse events. The study, which was originally planned to enroll 50 subjects in each group, was ended with insufficient recruitment. A total of 46 subjects completed the study, and analysis was conducted in this cohort. Reduction in HbA1c at week 24 was comparable between the metformin (n = 24) and liraglutide (n = 22) groups (-0.95 ± 0.80% vs. -0.80 ± 0.88%, p = 0.77), while the liraglutide group reached maximal reduction more rapidly than did the metformin group. There was no significant difference in weight gain or incidence of hypoglycemia between the groups. Diarrhea was more frequent in the metformin group, while constipation was more frequent in the liraglutide group. There was no significant difference in treatment satisfaction between the groups. In conclusion, liraglutide and metformin monotherapy showed similar reduction in HbA1c during 24 weeks, with no difference in weight gain or incidence of hypoglycemia in overweight or obese Japanese patients with T2DM.


The relationship between inadequate response to physical therapy and central sensitization in patients with knee osteoarthritis: A prospective cohort study.
Objectives: This study aims to investigate the relationship between physical therapy response and the presence of central sensitization (CS) in patients with painful knee osteoarthritis (OA). Patients and methods: Between May 2019 and March 2020, a total of 84 patients with knee OA (12 males, 72 females; mean age: 60.7±7.7 years; range 50 to 74 years) and 30 age and sex-matched controls (6 males, 24 females; mean age: 59.2±8.9 years; range 50 to 75 years) were included in this study. Knee pain and functional status were evaluated by Visual Analog Scale (VAS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Structural damage was assessed by knee radiography. The Central Sensitization Inventory (CSI), Beck Depression Inventory (BDI), Insomnia Severity Index (ISI), Pain Catastrophizing Scale (PCS), and PainDETECT Questionnaire (PDQ) were applied at baseline. Pain pressure thresholds (PPTs) of the patients were measured and compared with the control group. All patients underwent a total of 15 sessions of physical therapy program for five sessions/weekly. After treatment, the patients were divided into two groups as responders and non-responders according to the Osteoarthritis Research Society International (OARSI) criteria. Results: The CSI score of the patients in non-responder group was significantly higher compared to the responder group (p=0.004). Using a cut-off value of ≥40, the proportion of patients with CSI scores of ≥40 was significantly lower in the responder group compared to non-responder group (p=0.021). The PPT measurement values were significantly lower in the non-responder group compared to the responder and control groups (p <0.01). There was a significant difference in the frequency of hyperalgesia between the groups (p=0.021). Central sensitization and depression were the most significant predictors of non-response to physical therapy (p=0.045 and p=0.024, respectively). Conclusion: Our study results suggest the presence of CS and depression may result in an inadequate response to physical therapy in patients with knee OA. Clinicians should consider the findings of CS and depression in treatment planning.


Occult nodal disease in patients with failed laryngeal preservation undergoing surgical salvage.
The primary objective was to determine the incidence of pathologically positive lymph nodes in clinically N0 larynx cancer patients undergoing salvage surgery following nonsurgical primary therapy. Secondary aims included assessment of the impact of laryngeal subsite and neck dissection on disease status and survival. Retrospective chart review. Sixty-eight patients with recurrent laryngeal cancer and no evidence of neck disease who underwent salvage laryngectomy and neck dissection after undergoing failed primary radiotherapy or chemoradiation were examined. Main outcome measures included: standard demographics, primary, clinical, radiologic, and pathologic recurrent TNM stage, laryngeal subsite, nodal neck level, surgical intervention, margin status, disease status, survival, and imaging results. Fifty-three men and 15 women, aged 33 to 88 years (mean=62.7 years) with recurrent laryngeal cancer were included. Overall, 28.3% of patients had pathologic nodal disease, with supraglottic cancer showing the highest rate (60%, P=.02). Survival was not associated with laryngectomy type (P=.35). However, on multivariate analysis, laryngeal subsite was significantly predictive of survival with transglottic recurrences demonstrating decreased mean survival (20.7 months, P=.02), and supraglottic recurrences demonstrating prolonged mean survival (37.1 months, P=.03). Metabolic imaging (negative predictive value=0.86) proved more reliable than anatomic imaging (negative predictive value=0.71). The incidence of pathologically positive lymph nodes in clinically negative patients with recurrent laryngeal carcinoma following nonsurgical therapy warrants standard selective neck dissection. Subsite of recurrence, specifically supraglottis and transglottis, correlates with pathologic neck node positivity and survival. Metabolic imaging proved more reliable than anatomic imaging in negative predictability for nodal disease. 4.


Performance evaluation of a novel reciprocation membrane bioreactor (rMBR) for enhanced nutrient removal in wastewater treatment: a comparative study.
This study compared and evaluated the performance of a conventional membrane bioreactor (MBR) and a novel reciprocation MBR (rMBR) which used mechanical membrane reciprocation in place of membrane air scouring in pilot-scale tests. Each system was independently operated for 280 days at a local wastewater treatment plant for a parallel assessment of operating performance. The rMBR was found to be more effective than the MBR with regard to operating performance and energy consumption. Inertial forces created by the reciprocating motion shook foulants from the membrane surface. In addition, because of the looseness of the fibers, they moved relative to each other during reciprocation thus preventing sludge clogging inside the fiber bundle. Because the rMBR does not use aeration for membrane cleaning, the membrane tank in the rMBR maintained anoxic conditions, allowing endogenous denitrification in the membrane tank. The rMBR permeate contained an average of 1.7 mg/L total nitrogen (TN) with less than 1 mg/L NO(3)-N, while the TN concentration in the MBR permeate averaged 5 mg/L with 3.5 mg/L NO(3)-N. The specific energy consumption for membrane reciprocation in the rMBR was 0.064 kWh/m(3), while that for air scouring in the MBR was 0.19 kWh/m(3).


Global phylogeography and ancient evolution of the widespread human gut virus crAssphage.
Microbiomes are vast communities of microorganisms and viruses that populate all natural ecosystems. Viruses have been considered to be the most variable component of microbiomes, as supported by virome surveys and examples of high genomic mosaicism. However, recent evidence suggests that the human gut virome is remarkably stable compared with that of other environments. Here, we investigate the origin, evolution and epidemiology of crAssphage, a widespread human gut virus. Through a global collaboration, we obtained DNA sequences of crAssphage from more than one-third of the world's countries and showed that the phylogeography of crAssphage is locally clustered within countries, cities and individuals. We also found fully colinear crAssphage-like genomes in both Old-World and New-World primates, suggesting that the association of crAssphage with primates may be millions of years old. Finally, by exploiting a large cohort of more than 1,000 individuals, we tested whether crAssphage is associated with bacterial taxonomic groups of the gut microbiome, diverse human health parameters and a wide range of dietary factors. We identified strong correlations with different clades of bacteria that are related to Bacteroidetes and weak associations with several diet categories, but no significant association with health or disease. We conclude that crAssphage is a benign cosmopolitan virus that may have coevolved with the human lineage and is an integral part of the normal human gut virome.


Weekly exercise does not improve fatigue levels in Parkinson's disease.
Fatigue is one of the most disabling non-motor symptoms for people with Parkinson's disease. Exercise may modify fatigue. This study examines prescribed exercise effects on physical activity levels, well-being, and fatigue in Parkinson's disease. In this single-blinded trial, participants were randomly assigned to either a 12 week community exercise program or control group. Primary outcome measures were fatigue (Fatigue Severity Scale) and physical activity. Thirty-nine people with Parkinson's disease were included: 20 in exercise and 19 in control. Sixty-five percent of the study group were fatigued (n = 24, mean 4.02, SD 1.48). Increased fatigue was associated with lower mobility and activity (P < .05). Individuals participated in a mean of 15 (SD 10) exercise sessions with no significant change in fatigue, mobility, well-being, or physical activity after exercise (P ≥ .05). Participation in weekly exercise did not improve fatigue in people with Parkinson's Disease.


The occurrence of metacercariae of Petasiger (Digenea: Echinostomatidae) in an unusual site, within the lateral line scales of cyprinid fishes.
During a regular veterinary inspection of fishes from Lake Balaton, Hungary, echinostomatid metacercariae (Digenea), with collar spines characteristic of species of the genera Petasiger Dietz, 1909 and Paryphostomum Dietz, 1909, were found in the lateral line scales of a roach Rutilus rutilus (Linnaeus), an apparently unique site. In a subsequent examination of 586 fishes from 20 different species, similar infections were found in 11 species. The infection was virtually restricted to the lateral line scales, other scales being infected only incidentally. These encysted metacercariae had 27 collar spines, including eight larger angle spines and 19 smaller dorsal spines arranged in two rows. Two types of metacercarial cyst were found. One type had a cyst diameter of 138-171 µm × 105-120 µm and three central dorsal spines that were larger than the remainder and tended to resemble the angle spines. The second type of metacercarial cyst had a diameter of 128-157 µm × 105-115 µm and all 19 dorsal spines of the metacercaria were of a similar size. ITS sequences of the second type of metacercaria exhibited a 100% similarity to sequences of two adult Petasiger phalacrocoracis (Yamaguti, 1939) specimens collected from the gut of Phalacrocorax carbo (Linnaeus) in Hungary and to P. phalacrocoracis deposited in the GenBank database. Sequences obtained from two metacercariae of the first type showed a 2.8-2.9 % difference from sequences of the second type of metacercaria and from those of adult specimens of P. phalacrocoracis from cormorants. Based on these results, the second type metacercaria is considered to be a larval stage of P. phalacrocoracis, but the identity of the first type is uncertain. The unusual location of these metacercariae in the lateral line scales is discussed in relation to their transmission.


fromage: A library for the study of molecular crystal excited states at the aggregate scale.
The study of photoexcitations in molecular aggregates faces the twofold problem of the increased computational cost associated with excited states and the complexity of the interactions among the constituent monomers. A mechanistic investigation of these processes requires the analysis of the intermolecular interactions, the effect of the environment, and 3D arrangements or crystal packing on the excited states. A considerable number of techniques have been tailored to navigate these obstacles; however, they are usually restricted to in-house codes and thus require a disproportionate effort to adopt by researchers approaching the field. Herein, we present the FRamewOrk for Molecular AGgregate Excitations (fromage), which implements a collection of such techniques in a Python library complemented with ready-to-use scripts. The program structure is presented and the principal features available to the user are described: geometrical analysis, exciton characterization, and a variety of ONIOM schemes. Each is illustrated by examples of diverse organic molecules in condensed phase settings. The program is available at https://github.com/Crespo-Otero-group/fromage.


Resetting the biological clock: mediation of nocturnal circadian shifts by glutamate and NO.
Circadian rhythms of mammals are timed by an endogenous clock with a period of about 24 hours located in the suprachiasmatic nucleus (SCN) of the hypothalamus. Light synchronizes this clock to the external environment by daily adjustments in the phase of the circadian oscillation. The mechanism has been thought to involve the release of excitatory amino acids from retinal afferents to the SCN. Brief treatment of rat SCN in vitro with glutamate (Glu), N-methyl-D-aspartate (NMDA), or nitric oxide (NO) generators produced lightlike phase shifts of circadian rhythms. The SCN exhibited calcium-dependent nitric oxide synthase (NOS) activity. Antagonists of NMDA or NOS pathways blocked Glu effects in vitro, and intracerebroventricular injection of a NOS inhibitor in vivo blocked the light-induced resetting of behavioral rhythms. Together, these data indicate that Glu release, NMDA receptor activation, NOS stimulation, and NO production link light activation of the retina to cellular changes within the SCN mediating the phase resetting of the biological clock.


An update on the physiology of atrial natriuretic factor.
The atrial natriuretic factor (ANF) has pharmacological actions resulting in lower atrial and arterial pressures. Atrial distention stimulates ANF release, suggesting that ANF is an effector limb of a feedback loop for controlling cardiac filling pressure. To test this hypothesis it will be necessary to determine whether physiological atrial distention releases ANF in sufficient amounts to exert biological actions. Immunoblockade of endogenous ANF and attenuation of ANF release by atrial ablation inhibited volume-induced natriuresis in rats. Infusion of ANF in rats at doses mimicking those observed during experimental volume expansion produced a natriuresis sufficient to partly account for the volume-induced response. Infusion of ANF at doses expected to change plasma ANF levels minimally decreased arterial pressure in hypertensive rats over 7 days. In dogs, some studies suggest that increased plasma ANF levels following experimental changes in atrial pressure were not sufficient to exert acute cardiovascular or renal actions, whereas others support such a notion and indicate that ANF inhibited barostimulated renal renin release. This last action could alter arterial pressure in the long term by allowing sodium equilibrium at lower renal arterial pressure. Infusion of ANF in humans that produced plasma levels in the upper physiological range caused increased sodium excretion and decreased plasma renin activity. Although data are exiguous, justifying neither acceptance nor rejection of the hypothesis that ANF functions physiologically to regulate body fluid volume and arterial pressure, the current evidence slightly favors acceptance.


Laying the foundation for a Genomic Rosetta Stone: creating information hubs through the use of consensus identifiers.
Given the growing wealth of downstream information, the integration of molecular and non-molecular data on a given organism has become a major challenge. For micro-organisms, this information now includes a growing collection of sequenced genes and complete genomes, and for communities of organisms it includes metagenomes. Integration of the data is facilitated by the existence of authoritative, community-recognized, consensus identifiers that may form the heart of so-called information knuckles. The Genomic Standards Consortium (GSC) is building a mapping of identifiers across a group of federated databases with the aim to improve navigation across these resources and to enable the integration of their information in the near future. In particular, this is possible because of the existence of INSDC Genome Project Identifiers (GPIDs) and accession numbers, and the ability of the community to define new consensus identifiers such as the culture identifiers used in the StrainInfo.net bioportal. Here we outline (1) the general design of the Genomic Rosetta Stone project, (2) introduce example linkages between key databases (that cover information about genomes, 16S rRNA gene sequences, and microbial biological resource centers), and (3) make an open call for participation in this project providing a vision for its future use.


The effect of maternal diabetes on trace element status and fetal development in the rat.
Despite improvements in prenatal care, there is a high incidence of congenital malformations in diabetic pregnancies. Not only is the diabetic patient characterized by a disorder of total fuel metabolism, but abnormal trace element metabolism occurs as well. In the present study, maternal and fetal zinc (Zn), copper (Cu), manganese (Mn), iron (Fe), magnesium (Mg), and calcium (Ca) status has been studied in Sprague-Dawley (SD) and Wistar rats. In addition, the effect of maternal diabetes on fetal development was also investigated. Rats were injected 27 days before mating with streptozocin (STZ, 45 mg/kg) in citrate buffer. On day 20 of gestation, litters were taken by cesarean section. Fetuses from diabetic dams weighed less, and had shorter crown-rump lengths and larger placentas than fetuses from controls. Evaluation of fetal skeletal development revealed fewer calcified sternal sites, anterior phalanges and caudal vertebrae, and an increased frequency of malformations in fetuses of diabetic dams. In dams, diabetics had larger adrenals, kidneys, and liver, and smaller thymus. Abnormal trace element metabolism was evident in diabetic dams and their fetuses. Mn was elevated in maternal liver, kidney and placenta of diabetic animals as well as in fetal liver of pups from diabetic dams. Maternal Cu and Zn levels were also higher in the liver and kidney of diabetic rats. In contrast, fetal liver Zn from fetuses of diabetic mothers was significantly decreased when compared with controls. These results suggest that diabetes may have induced fetal Zn deficiency. If this deficiency is present during embryogenesis/organogenesis, this could be one of the mechanisms of the teratogenicity of the diabetic state.


Computational Psychometrics Meets Hollywood: The Complexity in Emotional Storytelling.
Expressions of emotions are pervasive in media, especially in movies. In this article, we focus on the emotional relationships of movie characters in narrative thought and emotional storytelling. Several studies examine emotion elicitation through movies, but there is a gap in scientific literature and in the practice to quantitatively consider emotions among the characters of a movie story, which in turn provide the basis of spectator emotion elicitation. Some might argument that the ultimate purpose of a movie is to elicit emotions in the viewers; however, we are highlighting that the path to emotional stimulation entails emotions among the characters composing a narrative and manipulating to enable the effective elicitation of viewers' emotions. Here we provided and tested an effective quantitative method for analyzing these relationships in emotional networks, which allow for a clear understanding of the effects of story changes on movie perceptions and pleasantness.


Structural and transcriptional features of the mouse spermatid genome.
A whole-mount electron microscope technique has allowed direct visualization of the transcription process in mouse spermatids. Thes observations have been supported by light and electron microscope autoradiographic techniques that employ [3H]uridine and [3H]arginine in attempts to clarify mechanisms of RNA synthesis and their relationship to nuclear histone changes throughout spermiogenesis. Early spermatid genomes are dispersed almost completely, whereas in later spermiogenic steps the posterior or flagellar nuclear region is readily dispersed and the anterior or subacrosomal nuclear region remains compact. Display of genome segments permits identification of regions where transcription complexes, presumably heterogeneous nuclear RNA species, are seen related to chromatin. These complexes appear as ribonucleoprotein chains, some of them of considerable length, decreasing progressively in number in late spermiogenic steps. This decrease coincides with diminishing rates of [3H]uridine incorporation. Two distinct patterns of chromatin have been identified: a beaded chromatin type associated with transcription complexes encounterd in early spermatids; and a smooth chromatin type not involved in transcriptive activity observed in advanced spermiogenic genomes. Protein particles staining densely with phosphotungstic acid become apparent in nuclei of spermatids after [3H]arginine incorporation becomes significant. There is no structural or autoradiographic evidence for the presence of nucleoli during spermiogenesis. From these data and from previous experimental findings, we conclude that: (a) spermatogonia, spermatocytes and Sertoli cells are transcriptionally expressed into heterogeneous nuclear RNA and preribosomal RNA species whereas transcription in spermatids is predominantly heterogeneous nuclear RNA; and (b) the modification of the chromatin patterns in late spermiogenic steps indicates a stabilized genome that restricts transcriptive functions.


A large-conductance K+ channel that is inhibited by the cytoskeleton in the smooth muscle cell line DDT1 MF-2.
1. DDT1 MF-2 smooth muscle cells responded to the bath application of histamine or ATP with an increase in the cytosolic Ca2+ concentration ([Ca2+]c) and the whole-cell K+ current, IK(BA). 2. In cell-attached patches, histamine (100 microM) activated currents through a 200 pS K+ channel ('BKA' channel). In the absence of agonists, the BKA channel was activated by excision of the patch. Both histamine and patch excision increased the channel activity (NPo; where N is the number of channels per patch and Po is the open probability) by reducing the long closures between the bursts of openings. 3. In inside-out patches, the BKA channel had a conductance of 201 +/- 4 pS (symmetrical solutions of 150 mM KCl, 2 mM MgCl2 and 2 mM EGTA). Replacement of K+ in the patch electrode by Na+, Li+ or Cs+ prevented the flow of inward currents and reduced the outward K+ conductance to 113 pS. 4. NPo was insensitive to changes in [Ca2+]c from 10 nM to 1 microM. NPo was also not modified either by cytosolic Na+, ATP, GTP, GTP gamma S, dithiothreitol or TEA (10 mM) or by extracellular 4-aminopyridine (5 mM), glibenclamide (20 microM) or TEA (10 mM). The BKA channel was blocked by 5 mM intracellular BaCl2 or by 10 nM extracellular iberiotoxin. 5. In cell-attached patches, BKA channel activity could be induced by 1 microM cytochalasin B, applied either through the patch pipette or in the bath solution. The effects of cytochalasin B, of patch excision, or of histamine on NPo were not additive but saturative. 6. Whole DDT1 MF-2 cells had resting potentials of -10 mV, dominated by the chloride conductance; the resting potential changed to -82 mV when the K+ conductance was increased by cytochalasin B or by histamine. The effects of cytochalasin B and histamine on IK(BA) were not additive but saturative. 7. We discuss the hypothesis that the interaction between the cytoskeleton and the BKA channel promotes the long channel closures; depolymerization of F-actin may constitute a mechanism by which the agonists histamine or ATP disinhibit BKA channel activity.


Imaging in vivo dynamics of sensory axon responses to CNS injury.
Axons in the adult mammalian brain and spinal cord fail to regenerate upon lesion. In vivo imaging serves as a tool to investigate the immediate response of axons to injury and how the same injured axons behave over time. Here, we describe the dynamic changes that injured sensory axons undergo and methods of imaging them in vivo. First, we explain how sensory axons in the dorsal column of the adult mouse spinal cord respond to axotomy. Then, we highlight practical considerations for implementing two-photon based in vivo imaging of these axons. Finally, we describe future directions for this technique, including the possibility of in vivo imaging of subcellular dynamics within the axon.


Evaluating the replicability of social science experiments in Nature and Science between 2010 and 2015.
Being able to replicate scientific findings is crucial for scientific progress1-15. We replicate 21 systematically selected experimental studies in the social sciences published in Nature and Science between 2010 and 201516-36. The replications follow analysis plans reviewed by the original authors and pre-registered prior to the replications. The replications are high powered, with sample sizes on average about five times higher than in the original studies. We find a significant effect in the same direction as the original study for 13 (62%) studies, and the effect size of the replications is on average about 50% of the original effect size. Replicability varies between 12 (57%) and 14 (67%) studies for complementary replicability indicators. Consistent with these results, the estimated true-positive rate is 67% in a Bayesian analysis. The relative effect size of true positives is estimated to be 71%, suggesting that both false positives and inflated effect sizes of true positives contribute to imperfect reproducibility. Furthermore, we find that peer beliefs of replicability are strongly related to replicability, suggesting that the research community could predict which results would replicate and that failures to replicate were not the result of chance alone.


The FAST-MI 2005-2010-2015 registries in the light of the COMPASS trial: The COMPASS criteria applied to a post-MI population.
The COMPASS trial assessed the impact of adding low dose rivaroxaban to aspirin in selected patients (pts). After an acute myocardial infarction (MI), when dual antiplatelet treatment is no longer needed, patients might be eligible for aspirin/rivaroxaban co-therapy. The characteristics and risks of such a population are unclear. Data were extracted from the FAST-MI 2005, 2010 and 2015 nationwide French registries. Characteristics and long-term mortality were compared according to COMPASS eligibility and between registry and trial populations. Among 9954 patients alive and free of events at one year, 4402 (44%) were classified as COMPASS-Like (i.e. meeting COMPASS inclusion and without exclusion criteria), 1720 (17%) COMPASS-Excluded (i.e. meeting any exclusion criterion) and 3832 (39%) Non-COMPASS (i.e. meeting neither COMPASS inclusion nor exclusion criteria). COMPASS-Like patients were at higher risk and had higher 5-year mortality compared with Non-COMPASS patients. COMPASS-Excluded patients had the highest mortality. COMPASS enrichment criteria defined a population at increased risk of death: eligible pts. had 40% higher 5-year adjusted mortality (Hazard Ratio = 1.40 [1.15; 1.70]), while excluded pts. had 57% higher risk (Hazard Ratio = 1.57 [1.25; 1.97]). Patients meeting the COMPASS criteria one year after MI differed from those included in the randomized trial. Based on the population included in the French FAST-MI registries, enrichment criteria used in COMPASS defined a population representing 44% of the overall population of MI patients surviving to one year, and these patients are at high risk of 5-year mortality. They were at higher risk compared to chronic stable vascular patients enrolled in the trial. Registered with Clinicaltrials.gov under the number: NCT00673036.