Metabolic flux response to phosphoglucose isomerase knock-out in Escherichia coli and impact of overexpression of the soluble transhydrogenase UdhA

Blocking glycolytic breakdown of glucose by inactivation of phosphoglucose isomerase (Pgi) in Escherichia coli led to a greatly reduced maximum specific growth rate. Examination of the operational catabolic pathways and their flux ratios using [U-13C6]glucose-labeling experiments and metabolic flux ratio analysis provide evidence for the pentose phosphate (PP) pathway as the primary route of glucose catabolism in the knock-out mutant. The resulting extensive flux through the PP pathway disturbs apparently the reducing power balance, since overexpression of the recently identified soluble transhydrogenase UdhA improves significantly the growth rate of the Pgi mutant. The presented results provide first evidence that UdhA restores the cellular redox balance by catalyzing electron transfer from NADPH to NAD

Larger than Life: Humans' Nonverbal Status Cues Alter Perceived Size

Social dominance and physical size are closely linked. Nonverbal dominance displays in many non-human species are known to increase the displayer's apparent size. Humans also employ a variety of nonverbal cues that increase apparent status, but it is not yet known whether these cues function via a similar mechanism: by increasing the displayer's apparent size.We generated stimuli in which actors displayed high status, neutral, or low status cues that were drawn from the findings of a recent meta-analysis. We then conducted four studies that indicated that nonverbal cues that increase apparent status do so by increasing the perceived size of the displayer. Experiment 1 demonstrated that nonverbal status cues affect perceivers' judgments of physical size. The results of Experiment 2 showed that altering simple perceptual cues can affect judgments of both size and perceived status. Experiment 3 used objective measurements to demonstrate that status cues change targets' apparent size in the two-dimensional plane visible to a perceiver, and Experiment 4 showed that changes in perceived size mediate changes in perceived status, and that the cue most associated with this phenomenon is postural openness.We conclude that nonverbal cues associated with social dominance also affect the perceived size of the displayer. This suggests that certain nonverbal dominance cues in humans may function as they do in other species: by creating the appearance of changes in physical size

Factors Associated with Revision Surgery after Internal Fixation of Hip Fractures

Background: Femoral neck fractures are associated with high rates of revision surgery after management with internal fixation. Using data from the Fixation using Alternative Implants for the Treatment of Hip fractures (FAITH) trial evaluating methods of internal fixation in patients with femoral neck fractures, we investigated associations between baseline and surgical factors and the need for revision surgery to promote healing, relieve pain, treat infection or improve function over 24 months postsurgery. Additionally, we investigated factors associated with (1) hardware removal and (2) implant exchange from cancellous screws (CS) or sliding hip screw (SHS) to total hip arthroplasty, hemiarthroplasty, or another internal fixation device. Methods: We identified 15 potential factors a priori that may be associated with revision surgery, 7 with hardware removal, and 14 with implant exchange. We used multivariable Cox proportional hazards analyses in our investigation. Results: Factors associated with increased risk of revision surgery included: female sex, [hazard ratio (HR) 1.79, 95% confidence interval (CI) 1.25-2.50; P = 0.001], higher body mass index (fo

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Metabolic flux response to phosphoglucose isomerase knock-out in Escherichia coli and impact of overexpression of the soluble transhydrogenase UdhA

ISSN:0378-1097ISSN:1574-6968ISSN:0168-6496ISSN:0920-8534ISSN:0168-644

The Nonverbal Communication of Positive Emotions: An Emotion Family Approach

This review provides an overview of the research on nonverbal expressions of positive emotions, organised into emotion families, that is, clusters sharing common characteristics. Epistemological positive emotions (amusement, relief, awe, and interest) are found to have distinct, recognisable displays via vocal or facial cues, while the agency-approach positive emotions (elation and pride) appear to be associated with recognisable visual, but not auditory, cues. Evidence is less strong for the prosocial emotions (love, compassion, gratitude, and admiration) in any modality other than touch, and there is little support for distinct recognisable signals of the savouring positive emotions (contentment, sensory pleasure, and desire). In closing, some limitations of extant work are noted and some proposals for future research are outlined

Glycoprotein IIb/IIIa inhibitor use in patients with acute myocardial infarction undergoing PCI: insights from the TRANSLATE ACS study

Introduction: Concomitant use of glycoprotein IIb/IIIa inhibitors (GPI) and P2Y inhibitors increases bleeding risk. How GPIs are being used with faster onset, higher potency P2Y inhibitors are unclear. Methods and results: We studied 11,781 myocardial infarction (MI) patients treated with percutaneous coronary intervention (PCI) at 233 hospitals in the TRANSLATE ACS study (2010–2012). We used propensity matching to compare 6-week major adverse cardiac events (MACE: death, recurrent MI, stroke, or unplanned revascularization) and BARC 2+ bleeding events between patients who did and did not receive planned GPI. Planned and bailout GPI were used in 4,983 (42.2%) and 229 (4.4%) MI patients undergoing PCI, respectively. Patients receiving planned GPI were younger (58 vs. 61 years), more likely to present with STEMI (62.6% vs. 45.4%) or have stent thrombosis (4.2% vs. 2.1%, all P 6 hr prior to PCI versus earlier (27.8% vs. 44.4%, both P < 0.01). After propensity matching, planned GPI use was not associated with any difference in MACE (6.4% vs. 5.5% OR 1.18; 95% CI: 0.99–1.57), however, the risk of BARC 2+ bleeding was higher in patients who received planned GPI (11.3% vs. 8.7%; OR 1.34; 95% CI: 1.13–1.59). Conclusion: Planned GPI use as reported by practicing physicians was prevalent between 2010 and 2012 and was associated with increased risk of bleeding but not lower MACE

Management of Persistent Angina After Myocardial Infarction Treated With Percutaneous Coronary Intervention: Insights From the TRANSLATE-ACS Study.

Angina has important implications for patients' quality of life and healthcare utilization. Angina management after acute myocardial infarction (MI) treated with percutaneous coronary intervention (PCI) is unknown.TRANSLATE-ACS (Treatment With Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) was a longitudinal study of MI patients treated with percutaneous coronary intervention at 233 US hospitals from 2010 to 2012. Among patients with self-reported angina at 6 weeks post-MI, we described patterns of angina and antianginal medication use through 1 year postdischarge. Of 10 870 percutaneous coronary intervention-treated MI patients, 3190 (29.3%) reported angina symptoms at 6 weeks post-MI; of these, 658 (20.6%) had daily/weekly angina while 2532 (79.4%) had monthly angina. Among patients with 6-week angina, 2936 (92.0%) received β-blockers during the 1 year post-MI, yet only 743 (23.3%) were treated with other antianginal medications. At 1 year, 1056 patients (33.1%) with 6-week angina reported persistent angina symptoms. Of these, only 31.2% had been prescribed non-β-blocker antianginal medications at any time in the past year. Among patients undergoing revascularization during follow-up, only 25.9% were on ≥1 non-β-blocker anti-anginal medication at the time of the procedure.Angina is present in one third of percutaneous coronary intervention-treated MI patients as early as 6 weeks after discharge, and many of these patients have persistent angina at 1 year. Non-β-blocker antianginal medications are infrequently used in these patients, even among those with persistent angina and those undergoing revascularization

Technical Bulletin No.: 33

Not AvailableNot AvailableNot Availabl