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ObjectivesTo explore posttranslational modifications (PTMs), including proteolytic activation, multimerization, complex formation and citrullination of gelatinases, in particular of gelatinase B/MMP-9, and to detect in gelatin-Sepharose affinity-purified synovial fluids, the presence of specific MMP proteoforms in relation to arthritis.MethodsLatent, activated, complexed and truncated gelatinase-A/MMP-2 and gelatinase B/MMP-9 proteoforms were detected with the use of zymography analysis to compare specific levels, with substrate conversion assays, to test net proteolytic activities and by Western blot analysis to decipher truncation variants. Citrullination was detected with enhanced sensitivity, by the use of a new monoclonal antibody against modified citrullines.ResultsAll MMP-9 and MMP-2 proteoforms were identified in archival synovial fluids with the use of zymography analysis and the levels of MMP-9 versus MMP-2 were studied in various arthritic diseases, including rheumatoid arthritis (RA). Secondly, we resolved misinterpretations of MMP-9 levels versus proteolytic activities. Thirdly, a citrullinated, truncated proteoform of MMP-9 was discovered in archival RA synovial fluid samples and its presence was corroborated as citrullinated hemopexin-less MMP-9 in a small prospective RA sample cohort.ConclusionSynovial fluids from rheumatoid arthritis contain high levels of MMP-9, including its truncated and citrullinated proteoform. The combination of MMP-9 as analyte and its PTM by citrullination could be of clinical interest, especially in the field of arthritic diseases.

Interleukin 7 (IL-7) is a cell growth factor with a central role in normal T cell development, survival and differentiation. The lack of IL-7-IL-7 receptor(R)-mediated signaling compromises lymphoid development, whereas increased signaling activity contributes to the development of chronic inflammation, cancer and autoimmunity. Gain-of-function alterations of the IL-7R and the signaling through Janus kinases (JAKs) and signal transducers and activators of transcription (STATs) are enriched in T cell acute lymphoblastic leukemia (T-ALL) and autocrine production of IL-7 by T-ALL cells is involved in the phenotypes of leukemic initiation and oncogenic spreading. Several IL-7-associated pathologies are also characterized by increased presence of matrix metalloproteinase-9 (MMP-9), due to neutrophil degranulation and its regulated production by other cell types. Since proteases secreted by neutrophils are known to modulate the activity of many cytokines, we investigated the interactions between IL-7, MMP-9 and several other neutrophil-derived proteases. We demonstrated that MMP-9 efficiently cleaved human IL-7 in the exposed loop between the α-helices C and D and that this process is delayed by IL-7 N-linked glycosylation. Functionally, the proteolytic cleavage of IL-7 did not influence IL-7Rα binding and internalization nor the direct pro-proliferative effects of IL-7 on a T-ALL cell line (HPB-ALL) or in primary CD8+ human peripheral blood mononuclear cells. A comparable effect was observed for the neutrophil serine proteases neutrophil elastase, proteinase 3 and combinations of neutrophil proteases. Hence, glycosylation and disulfide bonding as two posttranslational modifications influence IL-7 bioavailability in the human species: glycosylation protects against proteolysis, whereas internal cysteine bridging under physiological redox state keeps the IL-7 conformations as active proteoforms. Finally, we showed that mouse IL-7 does not contain the protease-sensitive loop and, consequently, was not cleaved by MMP-9. With the latter finding we discovered differences in IL-7 biology between the human and mouse species. ispartof: FRONTIERS IN IMMUNOLOGY vol:12 ispartof: location:Switzerland status: published

With ELISAs one detects the ensemble of immunoreactive molecules in biological samples. For biomolecules undergoing proteolysis for activation, potentiation or inhibition, other techniques are necessary to study biology. Here we develop methodology that combines immunosorbent sample preparation and nano-scale liquid chromatography-tandem mass spectrometry (nano-LC-MS/MS) for proteoform analysis (ISTAMPA) and apply this to the aglycosyl chemokine CXCL8. CXCL8, the most powerful human chemokine with neutrophil chemotactic and -activating properties, occurs in different NH2-terminal proteoforms due to its susceptibility to site-specific proteolytic modification. Specific proteoforms display up to 30-fold enhanced activity. The immunosorbent ion trap top-down mass spectrometry-based approach for proteoform analysis allows for simultaneous detection and quantification of full-length CXCL8(1-77), elongated CXCL8(-2-77) and all naturally occurring truncated CXCL8 forms in biological samples. For the first time we demonstrate site-specific proteolytic activation of CXCL8 in synovial fluids from patients with chronic joint inflammation and address the importance of sample collection and processing. ispartof: FRONTIERS IN IMMUNOLOGY vol:12 ispartof: location:Switzerland status: published

integration requires development of low thermal budget process modules. High-quality SiO 2 interfacial layer (IL), obtained up to now only by high-temperature (≥850°C) oxidation or exposure, is crucial for pMOS NBTI reliability. In unannealed IL’s grown at reduced temperatures, we show that unrelaxed interface strain induces high defect densities, with physics-based NBTI modeling suggesting excessive hydroxyl-E’ defect formation due to Si-O bond stretch. Based on ab-initio theoretical insights, we demonstrate an atomic hydrogen treatment to passivate SiO 2 defects at low temperatures (100-300°C), which is shown to be vastly more effective than high pressure molecular hydrogen exposure, and to yield an SiO 2 quality and reliability surpassing a 900°C oxide.

Matrix metalloproteinases (MMPs) are enzymes with critical roles in biology and pathology. Glycosylation, nitrosylation and proteolysis are known posttranslational modifications (PTMs) regulating intrinsically the activities of MMPs. We discovered MMP citrullination by peptidyl arginine deiminases (PADs) as a new PTM. Upon hypercitrullination, MMP-9 acquired a higher affinity for gelatin than control MMP-9. Furthermore, hypercitrullinated proMMP-9 was more efficiently activated by MMP-3 compared to control MMP-9. JNJ0966, a specific therapeutic inhibitor of MMP-9 activation, inhibited the activation of hypercitrullinated proMMP-9 by MMP-3 significantly less in comparison with control proMMP-9. The presence of citrullinated/homocitrullinated MMP-9 was detected in vivo in neutrophil-rich sputum samples of cystic fibrosis patients. In addition to citrullination of MMP-9, we report efficient citrullination of MMP-1 and lower citrullination levels of MMP-3 and MMP-13 by PAD2 in vitro. In conclusion, citrullination of MMPs is a new PTM worthy of additional biochemical and biological studies. ispartof: MATRIX BIOLOGY vol:95 pages:68-83 ispartof: location:Netherlands status: published

A fundamental part of the immune response to infection or injury is leukocyte migration. Matrix metalloproteinases (MMPs) are a class of secreted or cell-bound endopeptidases, implicated in every step of the process of inflammatory cell migration. Hence, specific inhibition of MMPs is an interesting approach to control inflammation. We evaluated the potential of a bivalent carboxylate inhibitor to selectively inhibit the trimeric proteoform of MMP-9 and compared this with a corresponding monovalent inhibitor. The bivalent inhibitor efficiently inhibited trimeric MMP-9 (IC50 = 0.1 nM), with at least 500-fold selectivity for MMP-9 trimers over monomers. Surprisingly, in a mouse model for chemotaxis, the bivalent inhibitor amplified leukocyte influxes towards lipopolysaccharide-induced inflammation. We verified by microscopic and flow cytometry analysis increased amounts of neutrophils. In a mouse model for endotoxin shock, mice treated with the bivalent inhibitor had significantly increased levels of MMP-9 in plasma and lungs, indicative for increased inflammation. In conclusion, we propose a new role for MMP-9 trimers in tempering excessive neutrophil migration. In addition, we have identified a small molecule inhibitor with a high selectivity for the trimeric proteoform of MMP-9, which will allow further research on the functions of MMP-9 proteoforms. ispartof: CELLS vol:9 issue:7 ispartof: location:Switzerland status: published

For the first time, ion implant was used to partially relax the tensile strain by half in the fully-depleted (FD) strained SOI (SSOl) so that SiGe pFETs with a higher compressive strain can be realized at a fixed Ge composition. This enables the co-integration of highly tensile-strained Si nFETs and compressive-strained SiGe pFETs on the same substrate, achieving significant improvement in electrical performance over the unstrained counterpart verified by both experiment and simulation results. We also propose a Comb-like strained SOI architecture to further boost RF performance, demonstrating peak $G_{\mathrm{m}}$ improved by 47% over unstrained n-type FinFET SOI, as well as an improvement of 22% and 36% for $f_{\mathrm{T}}$ and $f_{\max}$ , respectively, over n-type FinFETs SSOI.

Top tier devices in a 3D sequential integration are optimized using a low temperature process flow $( . Bi-axial tensile strained silicon is transferred without strain relaxation to boost the top tier nmos device performance by 40-50% over the unstrained silicon devices, recovering the performance loss from the low temperature processing when using extension-less device integration. Excimer laser anneal is also shown to effectively activate both n-type and p-type dopants in the extension of thin silicon film devices using optimized, CMOS compatible, laser exposure conditions. Laser anneal is fully compatible with a replacement metal gate (RMG) process flow and with selective source/drain (SD) epitaxy. The dopant activation level is preserved during the entire process flow which results in similar $\mathrm{I}_{\mathrm{on}}-\mathrm{I}_{\mathrm{off}}$ device performance for devices with laser and spike anneals. Excimer laser anneal benefits also from improved control short channel effects over spike annealing due to low dopant diffusion.

Proteases are a diverse group of hydrolytic enzymes, ranging from single-domain catalytic molecules to sophisticated multi-functional macromolecules. Human proteases are divided into five mechanistic classes: aspartate, cysteine, metallo, serine and threonine proteases, based on the catalytic mechanism of hydrolysis. As a protective mechanism against uncontrolled proteolysis, proteases are often produced and secreted as inactive precursors, called zymogens, containing inhibitory N-terminal propeptides. Protease propeptide structures vary considerably in length, ranging from dipeptides and propeptides of about 10 amino acids to complex multifunctional prodomains with hundreds of residues. Interestingly, sequence analysis of the different protease domains has demonstrated that propeptide sequences present higher heterogeneity compared with their catalytic domains. Therefore, we suggest that protease inhibition targeting propeptides might be more specific and have less off-target effects than classical inhibitors. The roles of propeptides, besides keeping protease latency, include correct folding of proteases, compartmentalization, liganding, and functional modulation. Changes in the propeptide sequence, thus, have a tremendous impact on the cognate enzymes. Small modifications of the propeptide sequences modulate the activity of the enzymes, which may be useful as a therapeutic strategy. This review provides an overview of known human proteases, with a focus on the role of their propeptides. We review propeptide functions, activation mechanisms, and possible therapeutic applications. ispartof: CRITICAL REVIEWS IN BIOCHEMISTRY AND MOLECULAR BIOLOGY vol:55 issue:2 pages:111-165 ispartof: location:England status: published

Current needs for reduced emissions and improved efficiency have motivated the study of the combustion of novel, oxygenated fuels. The scope of the present work is to experimentally and num...

BACKGROUND: The efficacy and safety of benralizumab, an interleukin-5 receptor alpha-directed cytolytic monoclonal antibody, for the prevention of exacerbations in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) are not known.METHODS: In the GALATHEA and TERRANOVA trials, we enrolled patients with COPD (at a ratio of approximately 2:1 on the basis of eosinophil count [≥220 per cubic millimeter vs. RESULTS: In GALATHEA, the estimates of the annualized exacerbation rate were 1.19 per year (95% confidence interval [CI], 1.04 to 1.36) in the 30-mg benralizumab group, 1.03 per year (95% CI, 0.90 to 1.19) in the 100-mg benralizumab group, and 1.24 per year (95% CI, 1.08 to 1.42) in the placebo group; the rate ratio as compared with placebo was 0.96 for 30 mg of benralizumab (P = 0.65) and 0.83 for 100 mg of benralizumab (P = 0.05). In TERRANOVA, the estimates of the annualized exacerbation rate for 10 mg, 30 mg, and 100 mg of benralizumab and for placebo were 0.99 per year (95% CI, 0.87 to 1.13), 1.21 per year (95% CI, 1.08 to 1.37), 1.09 per year (95% CI, 0.96 to 1.23), and 1.17 per year (95% CI, 1.04 to 1.32), respectively; the corresponding rate ratios were 0.85 (P = 0.06), 1.04 (P = 0.66), and 0.93 (P = 0.40). At 56 weeks, none of the annualized COPD exacerbation rate ratios for any dose of benralizumab as compared with placebo reached significance in either trial. Types and frequencies of adverse events were similar with benralizumab and placebo.CONCLUSIONS: Add-on benralizumab was not associated with a lower annualized rate of COPD exacerbations than placebo among patients with moderate to very severe COPD, a history of frequent moderate or severe exacerbations, and blood eosinophil counts of 220 per cubic millimeter or greater (Funded by AstraZeneca [GALATHEA and TERRANOVA] and Kyowa Hakko Kirin [GALATHEA]; GALATHEA and TERRANOVA ClinicalTrials.gov numbers, NCT02138916 and NCT02155660.).

The basic analog parameters of three splits of In x Ga1– x As nTFETs are analyzed for the first time. The first two splits are In0.53Ga0.47As devices with a 3-nm HfO2/1-nm Al2O3 and a 2-nm HfO2/1-nm Al2O3, while the last one is an In0.7Ga0.3As channel with a 3-nm HfO2/1-nm Al2O3 gate. The low equivalent oxide thickness improves the electrostatic coupling, enhancing ${I}_{{\text {DS}}}$ , and, consequently, also gm and ${A}_{V}$ , especially for higher $\text {V}_{{\text {GS}}}$ . The InGaAs tunnel field-effect transistors (TFETs) show compatible performance with Si TFETs, and have better performance than Si MOSFETs, making them useful for low-power and low-voltage analog applications. The highest efficiency is found using the combination of a 2-nm HfO2 with In0.53Ga0.47As, due to the 56-mV/dec subthreshold swing obtained. For all splits, the ${A}_{V}$ peak can be related to the ${V}_{{\text {GS}}}$ necessary for band-to-band tunneling to become the dominant transport mechanism.

Systemic Lupus Erythematosus (SLE) is a common and devastating autoimmune disease, characterized by a dysregulated adaptive immune response against intracellular antigens, which involves both autoreactive T and B cells. In SLE, mainly intracellular autoantigens generate autoantibodies and these assemble into immune complexes and activate the classical pathway of the complement system enhancing inflammation. Matrix metalloproteinase-9 (MMP-9) levels have been investigated in the serum of SLE patients and in control subjects. On the basis of specific studies, it has been suggested to treat SLE patients with MMP inhibitors. However, some of these inhibitors induce SLE. Analysis of LPR-/-MMP-9-/- double knockout mice suggested that MMP-9 plays a protective role in autoantigen clearance in SLE, but the effects of MMP-9 on immune complexes remained elusive. Therefore, we studied the role of MMP-9 in the clearance of autoantigens, autoantibodies and immune complexes and demonstrated that the lack of MMP-9 increased the levels of immune complexes in plasma and local complement activation in spleen and kidney in the LPR-/- mouse model of SLE. In addition, we showed that MMP-9 dissolved immune complexes from plasma of lupus-prone LPR-/-/MMP-9-/- mice and from blood samples of SLE patients. Surprisingly, autoantigens incorporated into immune complexes, but not immunoglobulin heavy or light chains, were cleaved by MMP-9. We discovered Apolipoprotein-B 100 as a new substrate of MMP-9 by analyzing the degradation of immune complexes from human plasma samples. These data are relevant to understand lupus immunopathology and side-effects observed with the use of known drugs. Moreover, we caution against the use of MMP inhibitors for the treatment of SLE. ispartof: FRONTIERS IN IMMUNOLOGY vol:10 ispartof: location:Switzerland status: published

We study the positive bias temperature instability (PBTI) of InGaAs tunnel-FETs (TFETs) with two different indium fractions (53% and 70%) and compare with reference MOSFETs, using the same gate stack. While identical threshold voltage instability is found irrespective of the device type, the subthreshold swing (SS) of the TFETs is found to be more robust against PBTI as compared with MOSFETs. With the aid of comprehensive TCAD simulations, we show that the SS of a TFET is intrinsically less sensitive to interface/oxide border traps, thanks to the narrow energy range swept by the channel Fermi level during the OFF-to-ON transition of the device operation. Moreover, only traps located within $\sim 20$ nm from the tunnel junction can affect the SS.

Made available in DSpace on 2018-11-26T15:30:03Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-07-01 Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) imec's Logic Device Program In this work, the impact of the diameter on vertical nanowire tunnel field effect transistors is analyzed focusing on the conduction mechanism and analog parameters, considering different conduction regimes. The diameter influence is investigated using experimental and simulation data. The impact of the diameter on the analog parameters is analyzed, considering both weak and strong conduction. For a smaller diameter, the impact of band-to-band tunneling (BTBT) on the device characteristics increases, showing opposite trends for weak and strong conduction. For strong conduction, a degradation of the intrinsic voltage gain occurs for very small diameters, because the device has less available area for the occurrence of tunneling. For weak conduction, the reduction of the diameter increases the BTBT along the channel/source junction without showing this degradation. Univ Sao Paulo, BR-05508010 Sao Paulo, Brazil Sao Paulo State Univ, BR-01049010 Sao Joao Da Boa Vista, Brazil IMEC, B-3010 Leuven, Belgium Katholieke Univ Leuven, Dept Elect Engn, B-3001 Leuven, Belgium Sao Paulo State Univ, BR-01049010 Sao Joao Da Boa Vista, Brazil

Propanal (C2H5CHO) is a crucial intermediate oxygenated species in hydrocarbons and oxygenated fuels combustion, thus motivating a better understanding of its kinetics. In this study, two premixed at flames of propanal/hydrogen/oxygen/argon, a stoichiometric and a rich, are stabilized at low pressure (27 mbar) on a burner. Species mole fraction profiles have been measured by molecular beam mass spectrometry (MBMS) for the reactants, products, and intermediate species: C2H5CHO (propanal), H2, O2, Ar, H, OH, HO2, CO, CO2, H2O, CH3, CH4, CH2O (formaldehyde), CH2CO (ketene), CH3CO (acetyl radical), C2H2 (acetylene), C2H4 (ethylene), and C2H6 (ethane). The mechanism from the Universite catholique de Louvain (UCL) has been extended to the kinetics of propanal and its reliability has been validated against both of these propanal flames, at low pressure and in the temperature range up to 1530 K. According to the model, the main propanal consumption channel produces the ethyl radical (C2H5). This last radi...

In the human body, the black-brown biopigment eumelanin blocks the harmful ultraviolet (UV) radiation. In the plastics industry, additives are often added to polymers to increase their UV-absorption properties. We herein report an assessment of the biopigment eumelanin as a nature-inspired additive for plastics to enhance their UV-absorption. Since eumelanin is produced by natural sources and is non-toxic, it is an interesting candidate in the field of sustainable plastic additives. In this work, eumelanin-including films of commercial ethylene-vinyl acetate copolymer (EVA), a plastic used for packaging applications, were obtained by melt-compounding and compression molding. The biopigment dispersion in the films was improved by means of the Melanin Free Acid treatment (MFA). It was observed that eumelanin amounts as low as 0.8% wt. cause an increase of the UV absorption, up to one order of magnitude in the UVA range. We also evaluated the effect of eumelanin on the thermal and photostability of the films: the biopigment proved to be double-edged, working both as UV-absorption enhancer and photo-prooxidant, as thermogravimetric analysis (TGA) and infrared (IR) spectroscopy revealed.

3 Dstacking using a sequential integration approach is demonstrated for finfet devices on 300mm wafers at a 45nm fin pitch and 110nm poly pitch technology. This demonstrates the compatibility of the 3D sequential approach for aggressive device density stacking at advanced nodes thanks to the tight alignment precision of the first processed top layer to the last processed bottom layer through the top silicon channel and bonding stack during 193nm immersion lithography. The top devices are junction-less devices fabricated at low temperature $(\mathrm{T}\leq 525^{\circ}\mathrm{C})$ in a top Si layer transferred by wafer-to-wafer bonding with a bonding dielectric stack down to 170nm. The top devices offer similar performance as the high temperature bulk finfet technology for LSTP applications. The use of TiN/TiA1/TiN/HfO 2 gate stack provides the proper threshold voltage adjustment while the insertion of the LaSiO x dipole improves device performance and brings the BTI reliability within specification at low temperature.

We investigate BTI charge trapping trends in high-k metal gate (HKMG) stacks with a variety of work function metals. Most BTI models suggest charge trapping in oxide defects is modulated by the applied oxide electric field, which controls the energy barrier for the capture process, irrespective of the metal work function. However, experimental data show enhanced or reduced charge trapping at constant oxide electric field for different work function metal stacks. We ascribe this to a different chemical interaction of the metal stack with the dielectric, yielding different defect profiles depending on the process thermal budget. Furthermore, by employing the imec/T.U. Wien physics-based BTI simulation framework “Comphy”, we also show that different metal work functions within a typical range of relevance (4.35-4.75eV) can yield a different charge state of the deep high-k defects, and can therefore have an impact on charge trapping kinetics during BTI stress, particularly in nMOSFETs.

FinFET has been introduced in the 22/16nm node to continue CMOS logic scaling. The very tight pitches foreseen for the coming generation necessitate the introduction of different scaling boosters. In this paper, we review how these elements affect the analog device performance. The benefits of alternative channel material for dedicated RF applications and the related integration challenges are also discussed.

Gelatin zymography analysis is a sensitive method and commonly used to characterize and quantify the presence of the gelatinases (MMP-2 and MMP-9) in biological samples. In human plasma samples from healthy controls and systemic lupus erythematosus (SLE) patients, we observed a gelatinolytic molecule at 80 kDa, suggestive for activated human MMP-9. However, by developing and using the EDTA/gelatin zymography method and after purification of the 80 kDa entity, we proved that this molecule was the C1s subunit of the complement system. The zymolytic capacity of C1s was validated and found to be enhanced, in the absence of calcium and in the presence of EDTA. Our findings indicate that for correct identification of gelatinolytic proteins in complex biological samples the use of EDTA/gelatin zymography for enzyme development is advised. In addition, by quantification of EDTA/gelatin zymography analysis and ELISA, we observed that the levels of C1s were higher in plasma and immune complexes of SLE patients than of healthy individuals. Therefore, our data imply that C1s may become a marker for the diagnosis of SLE. ispartof: JOURNAL OF CELLULAR AND MOLECULAR MEDICINE vol:23 issue:1 pages:576-585 ispartof: location:England status: published

© 2018 Gouwy, De Buck, Abouelasrar Salama, Vandooren, Knoops, Pörtner, Vanbrabant, Berghmans, Opdenakker, Proost, Van Damme and Struyf. Serum amyloid A1 (SAA1) is a prototypic acute phase protein, induced to extremely high levels by physical insults, including inflammation and infection. Human SAA and its NH 2 -terminal part have been studied extensively in the context of amyloidosis. By contrast, little is known about COOH-terminal fragments of SAA. Intact SAA1 chemoattracts leukocytes via the G protein-coupled receptor formyl peptide receptor like 1/formyl peptide receptor 2 (FPR2). In addition to direct leukocyte activation, SAA1 induces chemokine production by signaling through toll-like receptor 2. We recently discovered that these induced chemokines synergize with intact SAA1 to chemoattract leukocytes in vitro and in vivo. Gelatinase B or matrix metalloproteinase-9 (MMP-9) is also induced by SAA1 during infection and inflammation and processes many substrates in the immune system. We demonstrate here that MMP-9 rapidly cleaves SAA1 at a known consensus sequence that is also present in gelatins. Processing of SAA1 by MMP-9 at an accessible loop between two alpha helices yielded predominantly three COOH-terminal fragments: SAA1(52-104), SAA1(57-104), and SAA1(58-104), with a relative molecular mass of 5,884.4, 5,327.3, and 5,256.3, respectively. To investigate the effect of proteolytic processing on the biological activity of SAA1, we chemically synthesized the COOH-terminal SAA fragments SAA1(52-104) and SAA1(58-104) and the complementary NH 2 -terminal peptide SAA1(1-51). In contrast to intact SAA1, the synthesized SAA1 peptides did not induce interleukin-8/CXCL8 in monocytes or fibroblasts. Moreover, these fragments possessed no direct chemotactic activity for neutrophils, as observed for intact SAA1. However, comparable to intact SAA1, SAA1(58-104) cooperated with CXCL8 in neutrophil activation and migration, whereas SAA1(1-51) lacked this potentiating activity. This cooperative interaction between the COOH-terminal SAA1 fragment and CXCL8 in neutrophil chemotaxis was mediated by FPR2. Hence, proteolytic cleavage of SAA1 by MMP-9 fine tunes the inflammatory capacity of this acute phase protein in that only the synergistic interactions with chemokines remain to prolong the duration of inflammation. ispartof: Frontiers In Immunology vol:9 issue:JUN ispartof: location:Switzerland status: published

Antileukoproteinase or secretory leukocyte peptidase inhibitor is a small protein which protects the mucosal linings against excessive proteolysis, inflammation, and microbial infection. We discovered that gelatinase B or matrix metalloproteinase (MMP)-9, a secreted zinc-dependent endopeptidase typically found at sites of inflammation, destroys antileukoproteinase by cleavages within both of its two functional domains: the anti-microbial N-terminal and the anti-proteolytic C-terminal domains. Cleaved antileukoproteinase possessed a significantly lower ability to bind lipopolysaccharides (LPS) and a reduced capacity to inhibit neutrophil elastase (NE) activity. Whereas intact antileukoproteinase repressed proinflammatory transcript [prostaglandin-endoperoxide synthase 2 (PTGS2) and IL6] synthesis and protein secretion [e.g., of MMP-9] in human CD14+ blood monocytes stimulated with LPS, this effect was reduced or lost for cleaved antileukoproteinase. We demonstrated the in vivo presence of antileukoproteinase cleavage fragments in lower airway secretions of non-cystic fibrosis bronchiectasis patients with considerable levels of neutrophils and, hence, elastase and MMP-9 activity. As a comparison, other MMPs (MMP-2, MMP-7, and MMP-8) and serine proteases (NE, cathepsin G, and proteinase 3) were also able to cleave antileukoproteinase with similar or reduced efficiency. In conclusion, in specific mucosal pathologies, such as bronchiectasis, neutrophils, and macrophage subsets control local immune reactions by proteolytic regulation, here described as the balance between MMPs (in particular MMP-9), serine proteases and local tissue inhibitors. ispartof: Frontiers in Immunology vol:9 issue:MAY ispartof: location:Switzerland status: published

Interleukin 2 (IL-2) is critical for T cell development and homeostasis, being a key regulator of adaptive immune responses in autoimmunity, hypersensitivity reactions and cancer. Therefore, its abundance in serum and peripheral tissues needs tight control. Here, we described a new mechanism contributing to the immunobiology of IL-2. We demonstrated, both in biochemical and cell-based assays, that IL-2 is subject to proteolytic processing by neutrophil matrix metalloproteinase-9 (MMP-9). IL-2 fragments produced after cleavage by MMP-9 remained linked by a disulfide bond and displayed a reduced affinity for all IL-2 receptor subunits and a distinct pattern and timing of signal transduction. Stimulation of IL-2-dependent cells, including murine CTLL-2 and primary human regulatory T cells, with cleaved IL-2 resulted in significantly decreased proliferation. The concerted action of neutrophil proteases destroyed IL-2. Our data suggest that in neutrophil-rich inflammatory conditions in vivo, neutrophil MMP-9 may reduce the abundance of signaling-competent IL-2 and generate a fragment that competes with IL-2 for receptor binding, whereas the combined activity of granulocyte proteases has the potential to degrade and thus eliminate bioavailable IL-2.

When processing Si nanowire based Tunnel Field Effect Transistors (TFETS's), a significant reduction of B diffusion with decreasing nanowire diameter is observed and attributed to reduced transient enhanced diffusion close to the nanowire surface caused by the recombination and out-diffusion of excess self-interstitials. In this study, Ultra High Voltage Electron Microscopy (UHVEM) is used to study in situ the formation of self-interstitial clusters in nanowire based TFET containing samples prepared by Focused Ion Beam (FIB) thinning. Si nanowires with diameters ranging from 40 to 500 nm are irradiated in an UHVEM using different fluxes of 2 MeV electrons at temperatures between room temperature and 375 °C. A strong dependence of defect formation on nanowire radius and on dopant concentration and type is observed. The UHVEM observations are compared with simulations based on quasi-chemical reaction rate theory and with two dimensional dopant concentration distributions determined with high-vacuum Scanning Spreading Resistance Microscopy (SSRM). (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

Matrix metalloproteinases (MMPs) are secreted as proenzymes, containing propeptides that interact with the catalytic zinc, thereby controlling MMP activation. The MMP‐9 propeptide is unique in the MMP family because of its post‐translational modification with an N‐linked oligosaccharide. ProMMP‐9 activation by MMP‐3 occurs stepwise by cleavage of the propeptide in an aminoterminal (pro‐AT) and carboxyterminal (pro‐CT) peptide. We chemically synthesized aglycosyl pro‐AT and pro‐CT and purified recombinant glycosylated pro‐ATS f−9. First, we report new cleavage sites in the MMP‐9 propeptide by MMP‐3 and neutrophil elastase. Additionally, we demonstrated with the use of western blot analysis a higher resistance of glycosylated versus aglycosyl pro‐AT against proteolysis by MMP‐3, MMP‐9, meprin α, neutrophil elastase and by protease‐rich synovial fluids from rheumatoid arthritis patients. Moreover, we investigated the effect of glycosylation on proteolytic activation of human proMMP‐9 with the use of zymography and dye‐quenched gelatin cleavage analysis. Compared to recombinant Sf‐9 proMMP‐9 glycoforms, larger oligosaccharides of human neutrophil proMMP‐9 increased resistance against proteolytic activation. Additionally, proMMP‐9 from Congenital Disorder of Glycosylation patients, compared to healthy controls, showed a higher activation rate by MMP‐3. Finally, we demonstrated that glycan‐galectin‐3 interactions reduced proMMP‐9 activation. In conclusion, modification of MMP‐9 propeptide glycosylation is a fine‐tuning mechanism and co‐determines the specific activity of MMP‐9 in physiology and pathology. Enzymes MMP‐9 EC 3.4.24.35, MMP‐3 EC 3.4.24.17, meprin α EC 3.4.24.18, neutrophil elastase EC 3.4.21.37, trypsin EC 3.4.21.4 and PNGase F EC 3.5.1.52., Matrix metalloproteinases (MMPs) contain propeptides that interact with the catalytic zinc, thereby controlling MMP activation. The MMP‐9 propeptide (green) is unique within the MMP family having an N‐linked oligosaccharide (purple). We showed that MMP‐9 propeptide glycosylation itself and galectin‐3 (pink) binding are fine‐tuning mechanisms of the proteolytic activation process, by MMP‐3 (cyan), thereby co‐determining the specific activity of MMP‐9.

The addition of acetone to stoichiometric and rich hydrogen/oxygen/argon flames has been investigated by measuring the intermediate species concentrations. Two premixed acetone/hydrogen/oxygen/argon flames were stabilized at low pressure (27 mbar) on a Spalding-Botha type burner at two equivalence ratios, ϕ = 1.1 and 1.72. Identification and monitoring of signal intensity profiles of species within the flames were carried out using molecular beam mass spectrometry. The detected species throughout the flame thickness are CH3COCH3 (acetone), H2, O2, Ar, H, OH, CO, CO2, H2O, HO2, CH3, CH4, CH2O (formaldehyde), CH3CO (acetyl radical), C2H2 (acetylene) and C2H4 (ethylene). The mechanism from the Universite catholique de Louvain (UCL) has been extended to acetone kinetics, and has been assessed for these flames with a particular attention to the effect of the equivalence ratio on the intermediate species concentrations. Using this model, we established the main acetone degradation pathway in both flames at low pressure: CH3COCH3 → CH3COCH2 → CH2CO → CH3 → CH2O → HCO → CO → CO2.

In this work, the impact of the Zn diffusion processes in the source and the amount of Indium for In x Ga 1−x As nTFET was analyzed, focusing on the basic analog parameters. Three different splits were analyzed: In 0.53 Ga 0.47 As with Spin-on-Glass (SoG) Zn diffusion in the source, In 0.7 Ga 0.3 As using SoG and In 0.53 Ga 0.47 As with Gas Phase Zn diffusion in the source. The Ion increase of the Gas Phase device can be related to its higher source/channel junction abruptness that also reduces the tunneling length. The Gas Phase device has presented better subthreshold swing, which increases the transistor efficiency in the weak conduction regime. The Gas Phase device presents the lowest intrinsic voltage gain (A V )for high gate voltage (V GS ) values due to its significant output conductance (g D ) degradation However, the reduction of the temperature affects more g D than gm, resulting in an improvement of A V by more than 20 dB at 10 K for the Gas Phase device compared to both SoG splits.

3D Sequential integration has been envisioned to stack transistors in the same front-end process. A crucial challenge is the management of the thermal budget. This work focuses on Si nMOS gate stack challenges, specifically: for a top tier device, by inserting a thin LaSiO x interlayer between SiO 2 and HfO 2 a sufficient PBTI reliability is demonstrated without resorting to unsuitable high temperature anneals. This gate stack also offers good thermal stability for a pMOS over nMOS scenario.

In this work, the influence of the temperature and the different equivalent oxide thickness (EOT) of In 0.53 Ga 0.47 As nTFETs fabricated with gas phase Zn diffusion is analyzed. The different devices have in their gates stacks 3 nm of HfO 2 (with an EOT of 1 nm) or 2 nm of HfO 2 (with an EOT of 0.8 nm). The use of an EOT of 0.8 nm increases the band-to-band tunneling generation and also improves the subthreshold region characteristics, presenting a sub 60 mV/dec minimum subthreshold swing (56 mV/dec) at room temperature, resulting in better efficiency in weak conduction. Considering the temperature influence, the on-state current is less affected than the off-state current due to the band-to-band tunneling mechanism. In the subthreshold region the temperature decrease, which strongly reduces the off-state current, allows the band-to-band tunneling current to be more dominant, resulting in a better subthreshold swing and, consequently, a better transistor efficiency in the weak conduction regime. The opposite behavior occurs when heating the devices, reducing the influence of the band-to-band tunneling in the subthreshold region, degrading both the subthreshold swing and transistor efficiency in the weak conduction regime. In the strong conduction regime, the transistor follows the transconductance tendency, increasing for higher temperatures.

Retinopathy, a common cause of blindness, is a hallmark of diabetes and depends on two pathological mechanisms: vasculopathy and neuropathy. Whereas vasculopathy is well understood and has been associated with changes in gelatinase B/matrix metalloproteinase-9 (MMP-9) and other vasculotropic factors, specific markers for diabetes-induced retinal neuropathy are not yet described. Neuropathy may result from damages to the blood-retinal barrier (BRB) and from loss of neuroprotective factors. We studied diabetes-induced changes in vascular, inflammatory and regenerative markers and demonstrated that MMP-9 was increased, whereas prominin-1/CD133 was decreased in retinal extracts. In vitro, MMP-9 specifically destroyed prominin-1/CD133. Streptozotocin-induced diabetes resulted in BRB breakdown as a sign of vasculopathy and in prominin-1/CD133 destruction in photoreceptors as an in situ parameter of diabetic neuropathy. Both in vivo phenotypes were completely reversed in single MMP-9 gene knockout mice, demonstrating that MMP-9 mediates both diabetes-induced retinal vasculopathy and neuropathy, with prominin-1/CD133 being a critical and specific substrate of MMP-9. This functional link between gelatinase B/MMP-9 and prominin-1/CD133 explains mechanistically both the vasculopathy and neuropathy of diabetic retinopathy and suggests that specific MMP-9 inhibition is an interesting therapeutic avenue to investigate.

This paper presents a new integration scheme to fabricate a Si/Si0.55Ge0.45 heterojunction line tunnel field effect transistor (TFET). The device shows an increase in tunneling current with gate length. The 1- μm gate length device shows on current in excess of 20 μA/μm at VGS=VDS=1.2 V. Low-temperature measurements, performed to suppress trap-assisted tunneling (TAT), reveal the point subthreshold swing as low as 22 mV/dec at 78 K. Field-induced quantum confinement effects are found to increase the tunneling onset voltage by ~ 0.35 V. Variation of the tunneling onset voltage measured experimentally is correlated to variation in the pocket thickness and its doping concentration. Small geometry devices were found to be more susceptible to microvariations in the pocket thickness and doping concentration.

Specific cancer cell targeting is a pre-requisite for efficient drug delivery as well as for high-resolution imaging and still represents a major technical challenge. Tumor-associated enzyme-assisted targeting is a new concept that takes advantage of the presence of a specific activity in the tumor entity. MMP-9 is a protease found to be upregulated in virtually all malignant tumors. Consequently, we hypothesized that its presence can provide a de-shielding activity for targeted delivery of drugs by nanoparticles (NPs) in pancreatic cancer. Here, we describe synthesis and characterization of an optimized MMP-9-cleavable linker mediating specific removal of a PEG shield from a PLGA-b-PEG-based polymeric nanocarrier (Magh@PNPs-PEG-RegaCP-PEG) leading to specific uptake of the smaller PNPs with their cargo into cells. The specific MMP-9-cleavable linker was designed based on the degradation efficiency of peptides derived from the collagen type II sequence. MMP-9-dependent uptake of the Magh@PNPs-PEG-RegaCP-PEG was demonstrated in pancreatic cancer cells in vitro. Accumulation of the Magh@PNPs-PEG-RegaCP-PEG in pancreatic tissues in the clinically relevant KPC mouse model of pancreatic cancer, as a proof-of-concept, was tumor-specific and MMP-9-dependent, indicating that MMP-9 has a strong potential as a specific mediator of PNP de-shielding for tumor-specific uptake. Pre-treatment of mice with Magh@PNPs-PEG-RegaCP-PEG led to reduction of liver metastasis and drastically decreased average colony size. In conclusion, the increased tumor-specific presence and activity of MMP-9 can be exploited to deliver an MMP-9-activatable NP to pancreatic tumors specifically, effectively, and safely.

Background: Functionalized nanoparticles (NPs) are one promising tool for detecting specific molecular targets and combine molecular biology and nanotechnology aiming at modern imaging. We aimed at ligand-directed delivery with a suitable target-biomarker to detect early pancreatic ductal adenocarcinoma (PDAC). Promising targets are galectins (Gal), due to their strong expression in and on PDAC-cells and occurrence at early stages in cancer precursor lesions, but not in adjacent normal tissues. Results: Molecular probes (10-29 AA long peptides) derived from human tissue plasminogen activator (t-PA) were selected as binding partners to galectins. Affinity constants between the synthesized t-PA peptides and Gal were determined by microscale thermophoresis. The 29 AA-long t-PA-peptide-1 with a lactose-functionalized serine revealed the strongest binding properties to Gal-1 which was 25-fold higher in comparison with the native t-PA protein and showed additional strong binding to Gal-3 and Gal-4, both also over-expressed in PDAC. t-PA-peptide-1 was selected as vector moiety and linked covalently onto the surface of biodegradable iron oxide nanoparticles (NPs). In particular, CAN-doped maghemite NPs (CAN-Mag), promising as contrast agent for magnetic resonance imaging (MRI), were selected as magnetic core and coated with different biocompatible polymers, such as chitosan (CAN-Mag-Chitosan NPs) or polylactic co glycolic acid (PLGA) obtaining polymeric nanoparticles (CAN-Mag@PNPs), already approved for drug delivery applications. The binding efficacy of t-PA-vectorized NPs determined by exposure to different pancreatic cell lines was up to 90%, as assessed by flow cytometry. The in vivo targeting and imaging efficacy of the vectorized NPs were evaluated by applying murine pancreatic tumor models and assessed by 1.5 T magnetic resonance imaging (MRI). The t-PA-vectorized NPs as well as the protease-activated NPs with outer shell decoration (CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac) showed clearly detectable drop of subcutaneous and orthotopic tumor staining-intensity indicating a considerable uptake of the injected NPs. Post mortem NP deposition in tumors and organs was confirmed by Fe staining of histopathology tissue sections. Conclusions: The targeted NPs indicate a fast and enhanced deposition of NPs in the murine tumor models. The CAN-Mag@PNPs-PEG-REGAcp-PEG/tPA-pep1Lac interlocking steps strategy of NPs delivery and deposition in pancreatic tumor is promising.

The matrix metalloproteinases (MMPs) gelatinase A (MMP-2) and gelatinase B (MMP-9) are mediators of brain injury in multiple sclerosis (MS) and valuable biomarkers of disease activity. We applied bidimensional zymography (2-DZ) as an extension of classic monodimensional zymography (1-DZ) to analyse the complete pattern of isoforms and post-translational modifications of both MMP-9 and MMP-2 present in the sera of MS patients. The enzymes were separated on the basis of their isoelectric points (pI) and apparent molecular weights (Mw) and identified both by comparison with standard enzyme preparations and by Western blot analysis. Two MMP-2 isoforms, and at least three different isoforms and two different states of organization of MMP-9 (the multimeric MMP-9 and the N-GAL-MMP-9 complex) were observed. In addition, 2-DZ revealed for the first time that all MMP-9 and MMP-2 isoforms actually exist in the form of charge variants: four or five variants in the NGAL complex, more charge variants in the case of MMP-9; and five to seven charge variants for MMP-2. Charge variants were also observed in recombinant enzymes and, after concentration, also in sera from healthy individuals. Sialylation (MMP-9) and phosphorylation (MMP-2) contributed to molecular heterogeneity. The detection of charge variants of MMP-9 and MMP-2 in MS serum samples illustrates the power of 2-DZ and demonstrates that in previous studies MMP mixtures, rather than single molecules, were analysed. These observations open perspectives for better diagnosis and prognosis of many diseases and need to be critically interpreted when applying other methods for MS and other diseases. ispartof: Journal of Cellular and Molecular Medicine vol:18 issue:2 pages:242-252 ispartof: location:England status: published

This paper reports on the integration of vertical nTunnel FETs (TFETs) with SiGe hetero-junction and analyzes the presence of trap-assisted tunneling impacting the device behavior. Temperature measurements are used to distinguish the band-to-band tunneling (BTBT) from the trap-assisted tunneling (TAT). It is shown that TAT degrades the onset characteristic and the subthreshold swing of the devices. TCAD simulations are in good agreement with experimental data for a germanium content up to 44%, when including non-local TAT model and properly tuning the model’s parameters. Simulations also suggest that boosting the BTBT component, for example by further bandgap decrease (Ge source), or by other means should be beneficial in lowering the impact of trap-assisted tunneling, provided that the material defectivity does not worsen.

Gelatinase B or matrix metalloproteinase-9 (MMP-9) (EC 3.4.24.35) is increased in inflammatory processes and cancer, and is associated with disease progression. In part, this is due to MMP-9-mediated degradation of extracellular matrix, facilitating influx of leukocytes into inflamed tissues and invasion or metastasis of cancer cells. MMP-9 is produced as proMMP-9 and its propeptide is subsequently removed by other proteases to generate proteolytically active MMP-9. The significance of MMP-9 in pathologies triggered the development of specific inhibitors of this protease. However, clinical trials with synthetic inhibitors of MMPs in the fight against cancer were disappointing. Reports on active compounds which inhibit MMP-9 should be carefully examined in this regard. In a considerable set of recent publications, two antibiotics (minocycline and azythromycin) and the proteasome inhibitor bortezomib, used in cancers, were reported to inhibit MMP-9 at different stages of its expression, activation or activity. The current study was undertaken to compare and to verify the impact of these compounds on MMP-9. With exception of minocycline at high concentrations (>100 μM), the compounds did not affect processing of proMMP-9 into MMP-9, nor did they affect direct MMP-9 gelatinolytic activity. In contrast, azithromycin specifically reduced MMP-9 mRNA and protein levels without affecting NF-κB in endotoxin-challenged monocytic THP-1 cells. Bortezomib, although being highly toxic, had no MMP-9-specific effects but significantly upregulated cyclooxygenase-2 (COX-2) activity and PGE2 levels. Overall, our study clarified that azithromycin decreased the levels of MMP-9 by reduction of gene and protein expression while minocycline inhibits proteolytic activity at high concentrations. ispartof: PLoS One vol:12 issue:4 ispartof: location:United States status: published

Zymography is a technique for studying hydrolytic enzymes on the basis of substrate degradation. It is a powerful, but often misinterpreted, tool yielding information on potential hydrolytic activities, enzyme forms and the locations of active enzymes. In this Review, zymography techniques are compared in terms of advantages, limitations and interpretations. With in gel zymography, enzyme forms are visualized according to their molecular weights. Proteolytic activities are localized in tissue sections with in situ zymography. In vivo zymography can pinpoint proteolytic activity to sites in an intact organism. Future development of novel substrate probes and improvement in detection and imaging methods will increase the applicability of zymography for (reverse) degradomics studies.

This work reports for the first time on the experimental study of the intrinsic voltage gain of InGaAs nTFET. The influence of Indium/Gallium composition and Zn diffusion temperature is analyzed. For a higher Indium amount (In 0.7 Ga 0.3 As compared to In 0.53 Ga 0.47 As) the band to band tunneling (BTBT) is improved due to bandgap narrowing. A higher Zn diffusion temperature gives rise to a higher source doping, resulting in a smaller tunneling length, which also increases BTBT. In both devices the intrinsic voltage gain is improved. One interesting characteristic of these devices is that they present good analog performance at low voltages (V GS =V DS =0.6V), which is promising for low power/low voltage analog applications. High-temperature operation increases in all cases more the output conductance than the transconductance, resulting in a lower intrinsic voltage gain.

Iron oxide-containing magnetic nanoparticles (MNPs) have certain advantages over currently used contrast agents for tumor imaging by magnetic resonance imaging (MRI) as they offer the possibility of functionalization with ligands and tracers. Functionalized MNPs also may be used for targeted tumor therapy. In the current study nanoparticles (NPs) consisting of recombinant human serum albumin (rHSA) with incorporated hydrophilic (NH4)2Ce(IV)(NO3)6-γ-Fe2O3 particles (CAN maghemite particles) for medical imaging were produced and characterized. For this purpose CAN maghemite particles were incorporated into an rHSA matrix to yield rHSA-NPs. The resulting NPs were analyzed by transmission electron microscopy, photon correlation spectroscopy, and atomic absorption. The sizes of the manufactured NP were 170 ± 10 nm, and the zeta-potential was − 50 ± 3 mV. The NPs remained stable when stored after lyophilization with sucrose 3% [w/v] as a cryoprotector. They showed pro-inflammatory properties without cell and animal toxicity in vivo and were highly contrasting in MRI. In conclusion, this report introduces novel rHSA NP with favorable properties containing iron oxide for detection by MRI.

Current knowledge about the glycosylation of matrix metalloproteinases (MMPs) and the inhibitors of metalloproteinases (TIMPs) is reviewed. Whereas structural and functional aspects of the glycobiology of many MMPs is unknown, research on MMP-9 and MMP-14 glycosylation reveals important functional implications, such as altered inhibitor binding and cellular localization. This, together with the fact that MMPs contain conserved and many potential attachment sites for N-linked and O-linked oligosaccharides, proves the need for further studies on MMP glycobiology., Matrix metalloproteases (MMPs) are crucial components of a complex and dynamic network of proteases. With a wide range of potential substrates, their production and activity are tightly controlled by a combination of signalling events, zymogen activation, post-translational modifications and extracellular inhibition. Slight imbalances may result in the initiation or progression of specific disease states, such as cancer and pathological inflammation. As glycosylation modifies the structures and functions of glycoproteins and many MMPs contain N- or O-linked oligosaccharides, we examine, compare and evaluate the evidence for whether glycosylation affects MMP catalytic activity and other functions. It is interesting that the catalytic sites of MMPs do not contain O-linked glycans, but instead possess a conserved N-linked glycosylation site. Both N- and O-linked oligosaccharides, attached to specific protein domains, endow these domains with novel functions such as the binding to lectins, cell-surface receptors and tissue inhibitors of metalloproteases (TIMPs). Validated glycobiological data on N- and O-linked oligosaccharides of gelatinase B/MMP-9 and on O-linked structures of membrane-type 1 MMP/MMP-14 indicate that in-depth research of other MMPs may yield important insights, e.g. about subcellular localizations and functions within macromolecular complexes.

11 p.-5 fig.-1 tab., Degradation and remodeling of the extracellular matrix by matrix metalloproteinases (MMPs) plays important roles in normal development, inflammation, and cancer. MMP-9 efficiently degrades the extracellular matrix component gelatin, and the hemopexin domain of MMP-9 (PEX9) inhibits this degradation. To study the molecular basis of this inhibition, we generated GST fusion proteins containing PEX9 or truncated forms corresponding to specific structural blades (B1-B4) of PEX9. GST-PEX9 inhibited MMP-9-driven gelatin proteolysis, measured by gelatin zymography, FITC-gelatin conversion, and DQ-gelatin degradation assays. However, GST-PEX9 did not prevent the degradation of other MMP-9 substrates, such as a fluorogenic peptide, αB crystalline, or nonmuscular actin. Therefore, PEX9 may inhibit gelatin degradation by shielding gelatin and specifically preventing its binding to MMP-9. Accordingly, GST-PEX9 also abolished the degradation of gelatin by MMP-2, confirming that PEX9 is not an MMP-9 antagonist. Moreover, GST-B4 and, to a lesser extent, GST-B1 also inhibited gelatin degradation by MMP-9, indicating that these regions are responsible for the inhibitory activity of PEX9. Accordingly, ELISAs demonstrated that GST-B4 and GST-B1 specifically bound to gelatin. Our results establish new functions of PEX9 attributed to blades B4 and B1 and should help in designing specific inhibitors of gelatin degradation., This work was supported by Grant SAF2012-31613 and Red Temática de Investigación Cooperativa en Cáncer Grant RD12/0036/0061 from the Ministry of Economy and Competitivity (Spain) (to A. G.-P.); by Grant S2010/ BMD-2314 (to A. G.-P.) from the Comunidad de Madrid/European Union;and by the Concerted Research Actions Grant GOA 2013–2015 and the fund for Scientific Research of Flanders (to G. O.).

We report on the process integration of vertical silicon Tunnel FETs (TFETs) and analyze the impact of process and geometrical parameters on the device behavior. The gate–source overlap is shown to be a critical parameter, especially when the overlap is marginal. The temperature dependence also suggests that trap-assisted tunneling injection mechanism is at the origin of the degraded onset characteristic of the vertical TFET, likely due to a large interface trap density and that improvement in the passivation of the surface of the vertical nanowires should be beneficial.

Experimental mole fraction profiles of chemical species (stable, radical and intermediates) have been measured in three CH 3 COOH/O 2 /Ar flat premixed flames burning at low pressure (50mbar) and with equivalence ratios equal to 0.77, 0.9 and 1.05, respectively. The experimental setup used to determine the structure of one-dimensional laminar premixed flames consists of a molecular beam mass spectrometer system (MBMS) combined with electron impact ionisation (EI). Experimental results have highlighted an important role played by ketene (CH 2 CO) as an intermediate during the combustion of acetic acid. In order to simulate the experimental results, a sub-mechanism concerning the combustion of CH 3 COOH and CH 2 CO has been built and added to a global mechanism recently proposed. This ensures a reasonably good modelling for the structures of acetic acid flames. © 2011 The Combustion Institute.

We show the impact of process parameters on the electrical performance of complementary Multiple-Gate Tunnel Field Effect Transistors (MuGTFETs), implemented in a Multiple-Gate Field Effect Transistors (MuGFETs) technology compatible with standard CMOS processing. Firstly, we assess the impact of the gate oxide thickness on the tunneling performance. Secondly, we investigate the effect of the doping concentration and profile by implementing different doping conditions. Thirdly, three different annealing conditions are compared: spike anneal, sub-ms laser anneal and low temperature anneal for Solid Phase Epitaxy Regrowth (SPER). In case of SPER anneal a record drive current of 46 μA/μm at V DD of −1.2 V and I OFF of 5 pA/μm for Si pTFETs is reported. The enhanced current is given by the position of the silicide at the n+ side close to the gate. Silicide engineering opens a new opportunity to optimize tunnel devices.

Strain has been defined as a source of errors in the determination of heats of formations using bond separation reactions. In this work, we define Ring Conserving Isodesmic Reactions to conserve the strain. First a set of reference systems is defined to reproduce the different cyclic patterns. Those references are then used on bicyclohexadienes to evaluate the effect on the resulting heats of formation. In a last section, the successive heats of hydrogenation of the different systems are analyzed.

In this work, the isomerization mechanisms of dehydrofulvene radicals to the phenyl radical are described. This study shows, for 6-dehydrofulvene, a low-energy isomerization path going through a resonantly stabilized bicyclic system. In a second part, the different established mechanisms are applied to the closing of a second and third aromatic ring. This application highlights the possibility of forming new products, such as 2-naphthyl radical, and the effect of aromatic cycles on the new mechanisms.

The addition of dimethoxymethane (DMM or methylal) and diethoxymethane (DEM or ethylal) to a rich ethylene/oxygen/argon flame has been investigated by measuring the depletion of soot precursors. Three rich premixed ethylene/oxygen/argon (with and without added methylal or ethylal) flat flames have been stabilized at low-pressure (50 mbar) on a Spalding–Botha type burner with the same equivalence ratio of 2.50. Identification and monitoring of signal intensity profiles of species within the flames have been carried out by using molecular beam mass spectrometry (M.B.M.S.). The replacement of some C2H4 by C3H8O2 or C5H12O2 is responsible for a decrease of the maximum mole fractions of the detected intermediate species. This phenomenon is noticeable for C2–C4 intermediates and becomes more effective for C5–C10 species, mainly when C3H8O2 added. A new kinetic model has been elaborated and contains 546 reactions and 107 chemical species in order to simulate the three investigated flames: C2H4/O2/Ar, C2H4/DMM/O2/Ar and C2H4/DEM/O2/Ar. The reaction mechanism well reproduces experimental mole fraction profiles of major and intermediate species, and underlines the effect of methylal and ethylal addition on species concentration profiles for these flames.

International audience; The main objectives of this research consist in achieving both experimental and numerical studies of the combustion and oxidation of ethanol. Experimental mole fraction profiles of chemical species (stable, radical and intermediates) were measured in three C2H5OH/O2/Ar flat premixed flames stabilized at low pressure (50 mbar) and with equivalence ratios equal to 0.75, 1, and 1.25, respectively. The experimental setup used to determine the structure of one-dimensional laminar premixed flames consists of a molecular beam mass spectrometer system (MBMS) combined with electron impact ionization (EI). The oxidation of ethanol was also experimentally studied using a fused silica jet-stirred reactor (JSR). Experiments were performed in the temperature range 890-1250K, at 1 atm, at four equivalence ratios equal to 0.25, 0.5, 1 and 2 and with an initial fuel concentration of 0.2 mol %. A kinetic study was conducted in order to simulate all experimental data measured. It enabled building a kinetic mechanism by thoroughly reviewing the available literature and by taking into account specificities of the two kinds of experiments performed. Validity of the mechanism was also checked against experimental results previously published (ethanol oxidation in a JSR at 10 atm, ignition in a shock-tube, combustion in premixed, partially-premixed and non-premixed flames)). This mechanism ensures a reasonably good modelling of the combustion and oxidation of ethanol in the wide range of experimental conditions investigated.