PLIF Measurements of Nitric Oxide and Hydroxyl Radicals Distributions in Swirled Stratified Premixed Flames

Environmental and economic concerns have pushed aeronautical authorities to set stringent environmental regulations on fuel consumption, noise production, and pollutant emission. Engine manufacturers are developing novel staged injection concepts to ensure their respect. The injection staging creates a fuel-air mixture stratification involving new combustion processes not fully understood. This paper presents the experimental investigation of NO production for known swirled and / or stratified lean premixed flames. The fuel staging parameter defined as the stratification ratio is studied for values of 1, 2, and 3, while the swirl fractions are 0, 25 and 33%, changing the flowfield from non-swirling cond itions to high swirl numbers (up to 0.55). The implementation of simultaneous OH- and NOPLIF imaging techniques is achieved using high energy pulsed laser systems, able, for instance, to deliver 30 mJ/ pulse around the 226-nm UV wavelength for NO excitation. OH-PLIF is used to characterize the flame structure through the commonly extracted curvature, and also through the measurement of the flame thickness. These results show to be more accurate than thickness obtained from temperature profiles measured by Raman/ Rayleigh laser diagnostics. NO-PLIF is used to quantify the pollutant concentration. To this end, preliminary work was done to select the Q1 (29.5) transition as it the least temperature dependent excitation scheme with high fluorescence levels. After realizing a specific calibration of the NO-PLIF technique, the stud ied flames presented concentrations ranging from traces (20 ppm) to high levels (230 ppm). Further analysis of these results reveals that for high stratification ratios the prompt NO is favored and is responsible for the elevated level of NO pollutant

Septin 9_i2 is downregulated in tumors, impairs cancer cell migration and alters subnuclear actin filaments

International audienceFunctions of septin cytoskeletal polymers in tumorigenesis are still poorly defined. Their role in the regulation of cytokinesis and cell migration were proposed to contribute to cancer associated aneuploidy and metastasis. Overexpression of Septin 9 (Sept9) promotes migration of cancer cell lines. SEPT9 mRNA and protein expression is increased in breast tumors compared to normal and peritumoral tissues and amplification of SEPT9 gene was positively correlated with breast tumor progression. However, the existence of multiple isoforms of Sept9 is a confounding factor in the analysis of Sept9 functions. In the present study, we analyze the protein expression of Sept9_i2, an uncharacterized isoform, in breast cancer cell lines and tumors and describe its specific impact on cancer cell migration and Sept9 cytoskeletal distribution. Collectively, our results showed that, contrary to Sept9_i1, Sept9_ i2 did not support cancer cell migration, and induced a loss of subnuclear actin filaments. These effects were dependent on Sept9_i2 specific N-terminal sequence. Sept9_i2 was strongly down-regulated in breast tumors compared to normal mammary tissues. Thus our data indicate that Sept9_i2 is a negative regulator of breast tumorigenesis. We propose that Sept9 tumorigenic properties depend on the balance between Sept9_i1 and Sept9_i2 expression levels

Poly(I:C) induces intense expression of c-IAP2 and cooperates with an IAP inhibitor in induction of apoptosis in cancer cells

<p>Abstract</p> <p>Background</p> <p>There is increasing evidence that the toll-like receptor 3 (TLR3) is an interesting target for anti-cancer therapy. Unfortunately, most laboratory investigations about the impact of TLR3 stimulation on human malignant cells have been performed with very high concentrations - 5 to 100 μg/ml - of the prototype TLR3 ligand, poly(I:C). In a previous study focused on a specific type of human carcinoma - nasopharyngeal carcinoma - we have shown that concentrations of poly(I:C) as low as 100 ng/ml are sufficient to induce apoptosis of malignant cells when combined to a pharmacological antagonist of the IAP family based on Smac mimicry.</p> <p>Methods</p> <p>This observation prompted us to investigate the contribution of the IAP family in cell response to poly(I:C) in a variety of human malignant cell types.</p> <p>Results</p> <p>We report a rapid, intense and selective increase in c-IAP2 protein expression observed under stimulation by poly(I:C)(500 ng/ml) in all types of human malignant cells. In most cell types, this change in protein expression is underlain by an increase in c-IAP2 transcripts and dependent on the TLR3/TRIF pathway. When poly(I:C) is combined to the IAP inhibitor RMT 5265, a cooperative effect in apoptosis induction and/or inhibition of clonogenic growth is obtained in a large fraction of carcinoma and melanoma cell lines.</p> <p>Conclusions</p> <p>Currently, IAP inhibitors like RMT 5265 and poly(I:C) are the subject of separate therapeutic trials. In light of our observations, combined use of both types of compounds should be considered for treatment of human malignancies including carcinomas and melanomas.</p

Significance of Toll-like Receptors Expression in Tumor Growth and Spreading: A Short Review

Toll-like receptors (TLRs) are considered now as crucial sensors of innate immunity. Their role in the recognition of pathogens and the initiation of adaptive immune responses against them is well known. However, in last years TLRs have been identified on several tumor cells, including human malignancies. Their expression in cancer was found to be twofold: either promoting or inhibiting tumor progression. It was also demonstrated that several TLRs agonists, either natural or synthetic ones, may have beneficial effect on tumor-mediated disease, leading to potentiation of immune response to tumor-associated antigens. TLR-agonist linked tumor immunotherapy is still in nascent state, but growing rapidly, also in the area of common human malignancies. To date, the most promising and the most frequently studied interaction in tumor immunotherapy trials seems to be TLR9 and its synthetic agonists

Final analysis of a trial of M72/AS01E vaccine to prevent tuberculosis

Background Results of an earlier analysis of a trial of the M72/AS01E candidate vaccine against Mycobacterium tuberculosis showed that in infected adults, the vaccine provided 54.0% protection against active pulmonary tuberculosis disease, without evident safety concerns. We now report the results of the 3-year final analysis of efficacy, safety, and immunogenicity. Methods From August 2014 through November 2015, we enrolled adults 18 to 50 years of age with M. tuberculosis infection (defined by positive results on interferon-γ release assay) without evidence of active tuberculosis disease at centers in Kenya, South Africa, and Zambia. Participants were randomly assigned in a 1:1 ratio to receive two doses of either M72/AS01E or placebo, administered 1 month apart. The primary objective was to evaluate the efficacy of M72/AS01E to prevent active pulmonary tuberculosis disease according to the first case definition (bacteriologically confirmed pulmonary tuberculosis not associated with human immunodeficiency virus infection). Participants were followed for 3 years after the second dose. Participants with clinical suspicion of tuberculosis provided sputum samples for polymerase-chain-reaction assay, mycobacterial culture, or both. Humoral and cell-mediated immune responses were evaluated until month 36 in a subgroup of 300 participants. Safety was assessed in all participants who received at least one dose of M72/AS01E or placebo. Results A total of 3575 participants underwent randomization, of whom 3573 received at least one dose of M72/AS01E or placebo, and 3330 received both planned doses. Among the 3289 participants in the according-to-protocol efficacy cohort, 13 of the 1626 participants in the M72/AS01E group, as compared with 26 of the 1663 participants in the placebo group, had cases of tuberculosis that met the first case definition (incidence, 0.3 vs. 0.6 cases per 100 person-years). The vaccine efficacy at month 36 was 49.7% (90% confidence interval [CI], 12.1 to 71.2; 95% CI, 2.1 to 74.2). Among participants in the M72/AS01E group, the concentrations of M72-specific antibodies and the frequencies of M72-specific CD4+ T cells increased after the first dose and were sustained throughout the follow-up period. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. Conclusions Among adults infected with M. tuberculosis, vaccination with M72/AS01E elicited an immune response and provided protection against progression to pulmonary tuberculosis disease for at least 3 years. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598. opens in new tab.

Real-time intermembrane force measurements and imaging of lipid domain morphology during hemifusion

Membrane fusion is the core process in membrane trafficking and is essential for cellular transport of proteins and other biomacromolecules. During protein-mediated membrane fusion, membrane proteins are often excluded from the membrane-membrane contact, indicating that local structural transformations in lipid domains play a major role. However, the rearrangements of lipid domains during fusion have not been thoroughly examined. Here using a newly developed Fluorescence Surface Forces Apparatus (FL-SFA), migration of liquid-disordered clusters and depletion of liquid-ordered domains at the membrane-membrane contact are imaged in real time during hemifusion of model lipid membranes, together with simultaneous force-distance and lipid membrane thickness measurements. The load and contact time-dependent hemifusion results show that the domain rearrangements decrease the energy barrier to fusion, illustrating the significance of dynamic domain transformations in membrane fusion processes. Importantly, the FL-SFA can unambiguously correlate interaction forces and in situ imaging in many dynamic interfacial systems.open0

Prosthesis-patient mismatch after aortic valve replacement in the PARTNER 2 trial and registry

Objectives This study aimed to compare incidence and impact of measured prosthesis-patient mismatch (PPMM) versus predicted PPM (PPMP) after surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR). Background TAVR studies have used measured effective orifice area indexed (EOAi) to body surface area (BSA) to define PPM, but most SAVR series have used predicted EOAi. This difference may contribute to discrepancies in incidence and outcomes of PPM between series. Methods The study analyzed SAVR patients from the PARTNER (Placement of Aortic Transcatheter Valves) 2A trial and TAVR patients from the PARTNER 2 SAPIEN 3 Intermediate Risk registry. PPM was classified as moderate if EOAi ≤0.85 cm2/m2 (≤0.70 if obese: body mass index ≥30 kg/m2) and severe if EOAi ≤0.65 cm2/m2 (≤0.55 if obese). PPMM was determined by the core lab–measured EOAi on 30-day echocardiogram. PPMP was determined by 2 methods: 1) using normal EOA reference values previously reported for each valve model and size (PPMP1; n = 929 SAVR, 1,069 TAVR) indexed to BSA; and 2) using normal reference EOA predicted from aortic annulus size measured by computed tomography (PPMP2; n = 864 TAVR only) indexed to BSA. Primary endpoint was the composite of 5-year all-cause death and rehospitalization. Results The incidence of moderate and severe PPMP was much lower than PPMM in both SAVR (PPMP1: 28.4% and 1.2% vs. PPMM: 31.0% and 23.6%) and TAVR (PPMP1: 21.0% and 0.1% and PPMP2: 17.0% and 0% vs. PPMM: 27.9% and 5.7%). The incidence of severe PPMM and severe PPMP1 was lower in TAVR versus SAVR (P < 0.001). The presence of PPM by any method was associated with higher transprosthetic gradient. Severe PPMP1 was independently associated with events in SAVR after adjustment for sex and Society of Thoracic Surgeons score (hazard ratio: 3.18;95% CI: 1.69-5.96; P < 0.001), whereas no association was observed between PPM by any method and outcomes in TAVR. Conclusions EOAi measured by echocardiography results in a higher incidence of PPM following SAVR or TAVR than PPM based on predicted EOAi. Severe PPMP is rare (<1.5%), but is associated with increased all-cause death and rehospitalization after SAVR, whereas it is absent following TAVR

Poly I:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 3 (TLR3) is a critical component of the innate immune response to dsRNA viruses, which was considered to be mainly expressed in immune cells and some endothelial cells. In this study, we investigated the expression and proapoptotic activity of TLR3 in human and murine tumor cell lines.</p> <p>Methods</p> <p>RT-PCR and FACS analysis were used to detect expression of TLR3 in various human and murine tumor cell lines. All tumor cell lines were cultured with poly I:C, CHX, or both for 12 h, 24 h, 72 h, and then the cell viability was analyzed with CellTiter 96^®AQueous One Solution, the apoptosis was measured by FACS with Annexin V and PI staining. Production of Type I IFN in poly I:C/CHX mediated apoptosis were detected through western blotting. TLR3 antibodies and IFN-β antibodies were used in Blockade and Neutralization Assay.</p> <p>Results</p> <p>We show that TLR3 are widely expressed on human and murine tumor cell lines, and activation of TLR3 signaling in cancerous cells by poly I:C made Hela cells (human cervical cancer) and MCA38 cells (murine colon cancer) become dose-dependently sensitive to protein synthesis inhibitor cycloheximide (CHX)-induced apoptosis. Blockade of TLR3 recognition with anti-TLR3 antibody greatly attenuated the proapoptotic effects of poly I:C on tumor cells cultured with CHX. IFN-β production was induced after poly I:C/CHX treatment and neutralization of IFN-β slightly reduced poly I:C/CHX -induced apoptosis.</p> <p>Conclusion</p> <p>Our study demonstrated the proapoptotic activity of TLR3 expressed by various tumor cells, which may open a new range of clinical applications for TLR3 agonists as an adjuvant of certain cancer chemotherapy.</p

The academy for future science faculty:randomized controlled trial of theory-driven coaching to shape development and diversity of early-career scientists

Background: Approaches to training biomedical scientists have created a talented research community. However, they have failed to create a professional workforce that includes many racial and ethnic minorities and women in proportion to their representation in the population or in PhD training. This is particularly true at the faculty level. Explanations for the absence of diversity in faculty ranks can be found in social science theories that reveal processes by which individuals develop identities, experiences, and skills required to be seen as legitimate within the profession. Methods/Design: Using the social science theories of Communities of Practice, Social Cognitive Career Theory, identity formation, and cultural capital, we have developed and are testing a novel coaching-based model to address some of the limitations of previous diversity approaches. This coaching intervention (The Academy for Future Science Faculty) includes annual in-person meetings of students and trained faculty Career Coaches, along with ongoing virtual coaching, group meetings and communication. The model is being tested as a randomized controlled trial with two cohorts of biomedical PhD students from across the U.S., one recruited at the start of their PhDs and one nearing completion. Stratification into the experimental and control groups, and to coaching groups within the experimental arms, achieved equal numbers of students by race, ethnicity and gender to the extent possible. A fundamental design element of the Academy is to teach and make visible the social science principles which highly influence scientific advancement, as well as acknowledging the extra challenges faced by underrepresented groups working to be seen as legitimate within the scientific communities. Discussion: The strategy being tested is based upon a novel application of the well-established principles of deploying highly skilled coaches, selected and trained for their ability to develop talents of others. This coaching model is intended to be a complement, rather than a substitute, for traditional mentoring in biomedical research training, and is being tested as such

The Toll-Like Receptor Signaling Molecule Myd88 Contributes to Pancreatic Beta-Cell Homeostasis in Response to Injury

Commensal flora and pathogenic microbes influence the incidence of diabetes in animal models yet little is known about the mechanistic basis of these interactions. We hypothesized that Myd88, an adaptor molecule in the Toll-like-receptor (TLR) pathway, regulates pancreatic β-cell function and homeostasis. We first examined β-cells histologically and found that Myd88−/− mice have smaller islets in comparison to C57Bl/6 controls. Myd88−/− mice were nonetheless normoglycemic both at rest and after an intra-peritoneal glucose tolerance test (IPGTT). In contrast, after low-dose streptozotocin (STZ) challenge, Myd88−/−mice had an abnormal IPGTT relative to WT controls. Furthermore, Myd88−/− mice suffer enhanced β-cell apoptosis and have enhanced hepatic damage with delayed recovery upon low-dose STZ treatment. Finally, we treated WT mice with broad-spectrum oral antibiotics to deplete their commensal flora. In WT mice, low dose oral lipopolysaccharide, but not lipotichoic acid or antibiotics alone, strongly promoted enhanced glycemic control. These data suggest that Myd88 signaling and certain TLR ligands mediate a homeostatic effect on β-cells primarily in the setting of injury