| 1. |
- Andersson, KM, et al.
(författare)
-
GGTASE DEFICIENT MACROPHAGES ALTER INTEGRIN EXPRESSION ON LYMPHOCYTES AND FACILITATE DEVELOPMENT OF ARTHRITIS
- 2020
-
Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 79, s. 205-206
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Geranylgeranyltransferase type I (GGTaseI) is the enzyme responsible for the prenylation/ lipidation of the RhoA family proteins, which keeps them attached to the cell membrane. We reported that GGTaseI-deficient (GLC) mice develop a spontaneous and age-dependent arthritis, reproducing the pathology of RA1. Targeting GGTaseI activates RhoA proteins.Objectives:To study which of the activated Rho proteins is responsible for development of arthritis, we deleted individual RhoA, Rac1 or Cdc42 genes in GLC mice. We study consequences of GGTaseI deficiency for lymphocyte function.Methods:Double deficient mice that lack Rac1 (GLC Rac1fl/fl), RhoA (GLC RhoAfl/fl) and Cdc42 (GLC Cdc42fl/fl) were developed by Cre-technology using the LysM-promotor, and were on a mixed genetic background (129Ola/Hsd-C57BL/6)2. Joints of the hind paws were assessed for signs of arthritis histologically and by micro CT at age of 16 weeks. Phenotype of spleen CD4 and CD8 T cells was analysis by flow cytometry. Proliferation and cytokine production was assessed in spleen cultures by ELISA. Gene expression profile was analyzed by RT-PCR.Results:Deletion of Rho proteins had divergent effect on development of arthritis in GLC mice. We observed a reduction of the arthritis index in GLC Rac1fl/fl (n=19, p=0.027) and GLC RhoAfl/fl (n=4, p=0.007) mice compared to GLC (n=16), while GLC Cdc42fl/fl (n=4) had no change in arthritis development. GLC RhoAfl/fl mice increased the bone mass compared to GLC (p=0.029).Flow cytometry analysis showed that RA-prone GLC and GLC Cdc42fl/fl mice had lower number of CD4 cells in spleen. CD4 cells of RA-prone GLC and GLC Cdc42 mice had significantly higher subsets of the regulatory FoxP3+ and FOXp3+CD25+ cells (p=0.016-0.029 and p=0.016-0.029 respectively) compared to control and GLC RhoAfl/fl mice. Additionally, RA-prone mice had higher expression of receptors to extracellular matrix proteins collagen (α2β2) and fibronectin (α5β1) compared to control mice (p=0.016 and p=0.011 resp) and to RA-protected mice (GLC Rac1fl/fl and GLC RhoAfl/fl, p=0.0004 and p=0.011, resp). In total, both the number of FoxP3+ CD4 cells and the expression of α5β1 receptors on CD4 cells correlated strongly with the synovitis score (r=0.72, p=0.0017 and r=0.59, p=0.012, respectively).GGTaseI gene lays under the control of HOX proteins essential for cell homing. Importantly, HOX regulate the expression of integrins. Studying the expression of HoxA genes in spleen, we found that RA prone GLC and GLC Cdc42 mice tended to have lower expression of HoxA2 and higher expression of HoxA9 compared to RA-protected GLC Rac1 and GLC RhoA and to control mice. The Hoxa9/Hoxa2 ratio was significantly higher in RA prone mice compared to RA-protected mice (p=0.0085) and control mice (p=0.019). This ratio correlated with α5β1 receptors (r=0.55, p=0.0084), FOXP3+ CD4 cells (r=0.50, p=0.017), and the arthritis index (r=0.50, p=0.033).Conclusion:Taken together this study shows that Rho proteins play divergent role in development of arthritis. Activation of Rac1 and RhoA by GGTaseI deletion changes the pattern of HOXA proteins and increases expression of integrin receptors, which facilitates leukocyte influx in the paw joints. Deletion of Rac1 and RhoA has RA-protective effect in GLC mice.References:[1]Khan, O.M., et al.J Clin Invest121, 628 (2011).[2]Akula, M.K., et al.Nat Commun10, 3975 (2019).Disclosure of Interests:None declared
|
|
| 2. |
- Babayev, Rafig, et al.
(författare)
-
Computational characterization of hydrogen direct injection and nonpremixed combustion in a compression-ignition engine
- 2021
-
Ingår i: International Journal of Hydrogen Energy. - : Elsevier BV. - 0360-3199. ; 46:35, s. 18678-18696
-
Tidskriftsartikel (refereegranskat)abstract
- With the revived interest in hydrogen (H ) as a direct combustion fuel for engine applications, a computational study is conducted to assess the characteristics of H direct-injection (DI) compression-ignition (CI) non-premixed combustion concept. Development of a CFD modeling using CONVERGE CFD solver focuses on hydrogen's unique characteristics by utilizing a suitable numerical method to reproduce the direct H injection phenomena. A grid sensitivity study is performed to ensure the fidelity of results with optimal cost, and the models are validated against constant-volume optical chamber and diesel engine experimental data. The present study aims to contribute to the future development of DICI H combustion engines, providing detailed characterization of the combustion cycle, and highlighting several distinct aspects of CI nonpremixed H versus diesel combustion. First, unlike the common description of diesel sprays, hydrogen jets do not exhibit significant flame lift-off and air entrainment near injector nozzle, and the fuel-air interface is drastically more stratified with no sign of premixing. It is also found that the DICI H combustion concept is governed first by a free turbulent jet mixing phase, then by an in-cylinder global mixing phase. The former is drastically more dominant with the DICI H engine compared to conventional diesel engines. The free-jet mixing is also found to be more effective that the global mixing, which indicates the need to completely rethink the optimization strategies for CI engines when using H as fuel. 2 2 2 2 2 2 2 2
|
|
| 3. |
- Babayev, Rafig, 1995, et al.
(författare)
-
Computational comparison of the conventional diesel and hydrogen direct-injection compression-ignition combustion engines
- 2022
-
Ingår i: Fuel. - : Elsevier BV. - 0016-2361. ; 307
-
Tidskriftsartikel (refereegranskat)abstract
- Most research and development on hydrogen (H2) internal combustion engines focus on premixed-charge spark ignition (SI) or diesel-hydrogen dual-fuel technologies. Premixed charge limits the engine efficiency, power density, and safety, while diesel injections give rise to CO2 and particulate emissions. This paper demonstrates a non-premixed compression-ignition (CI) neat H2 engine concept that uses H2 pilots for ignition. It compares the CI H2 engine to an equivalent diesel engine to draw fundamental insights about the mixing and combustion processes. The Converge computational fluid dynamics solver is used for all simulations. The results show that the brake thermal efficiency of the CI H2 engine is comparable or higher than diesel, and the molar expansion with H2 injections at TDC constitutes 5–10 % of the total useful work. Fuel-air mixing in the free-jet phase of combustion is substantially higher with H2 due to hydrogen's gaseous state, low density, high injection velocity, and transient vortices, which contribute to the 3 times higher air entrainment into the quasi-steady-state jet regions. However, the H2 jet momentum is up to 4 times lower than for diesel, which leads to not only ineffective momentum-driven global mixing but also reduced heat transfer losses with H2. The short H2 flame quenching distance may also be inconsequential for heat transfer in CI engines. Finally, this research enables future improvements in CI H2 engine efficiency by hypothesizing a new optimization path, which maximizes the free-jet phase of combustion, hence is totally different from that for conventional diesel engines.
|
|
| 4. |
- Babayev, Rafig, 1995, et al.
(författare)
-
Computational optimization of a hydrogen direct-injection compression-ignition engine for jet mixing dominated nonpremixed combustion
- 2022
-
Ingår i: International Journal of Engine Research. - : SAGE Publications. - 1468-0874 .- 2041-3149. ; 23:5, s. 754-768
-
Tidskriftsartikel (refereegranskat)abstract
- Hydrogen (H2) nonpremixed combustion has been showcased as a potentially viable and preferable strategy for direct-injection compression-ignition (DICI) engines for its ability to deliver high heat release rates and low heat transfer losses, in addition to potentially zero CO2 emissions. However, this concept requires a different optimization strategy compared to conventional diesel engines, prioritizing a combustion mode dominated by free turbulent jet mixing. In the present work, this optimization strategy is realized and studied computationally using the CONVERGE CFD solver. It involves adopting wide piston bowl designs with shapes adapted to the H2 jets, altered injector umbrella angle, and an increased number of nozzle orifices with either smaller orifice diameter or reduced injection pressure to maintain constant injector flow rate capacity. This work shows that these modifications are effective at maximizing free-jet mixing, thus enabling more favorable heat release profiles, reducing wall heat transfer by 35%, and improving indicated efficiency by 2.2 percentage points. However, they also caused elevated incomplete combustion losses at low excess air ratios, which may be eliminated by implementing a moderate swirl, small post-injections, and further optimized jet momentum and piston design. Noise emissions with the optimized DICI H2 combustion are shown to be comparable to those from conventional diesel engines. Finally, it is demonstrated that modern engine concepts, such as the double compression-expansion engine, may achieve around 56% brake thermal efficiency with the DICI H2 combustion, which is 1.1 percentage point higher than with diesel fuel. Thus, this work contributes to the knowledge base required for future improvements in H2 engine efficiency.
|
|
| 5. |
- Babayev, Rafig, 1995, et al.
(författare)
-
Double compression-expansion engine (DCEE) fueled with hydrogen: Preliminary computational assessment
- 2022
-
Ingår i: Transportation Engineering. - : Elsevier BV. - 2666-691X. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Hydrogen (H2) is currently a highly attractive fuel for internal combustion engines (ICEs) owing to the prospects of potentially near-zero emissions. However, the production emissions and cost of H2 fuel necessitate substantial improvements in ICE thermal efficiency. This work aims to investigate a potential implementation of H2 combustion in a highly efficient double compression-expansion engine (DCEE). DICI nonpremixed H2 combustion mode is used for its superior characteristics, as concluded in previous studies. The analysis is performed using a 1D GT-Power software package, where different variants of the DICI H2 and diesel combustion cycles, obtained experimentally and numerically (3D CFD) are imposed in the combustion cylinder of the DCEE. The results show that the low jet momentum, free jet mixing dominated variants of the DICI H2 combustion concept are preferred, owing to the lower heat transfer losses and relaxed requirements on the fuel injection system. Insulation of the expander and removal of the intercooling improve the engine efficiency by 1.3 and 0.5%-points, respectively, but the latter leads to elevated temperatures in the high-pressure tank, which makes the selection of its materials harder but allows the use of cheaper oxidation catalysts. The results also show that the DCEE performance is insensitive to combustion cylinder temperatures, making it potentially suitable for other high-octane fuels, such as methane, methanol, ammonia, etc. Finally, a brake thermal efficiency of 56% is achieved with H2 combustion, around 1%-point higher than with diesel. Further efficiency improvements are also possible with a fully optimized H2 combustion system.
|
|
| 6. |
- Babayev, Rafig, 1995, et al.
(författare)
-
Hydrogen double compression-expansion engine (H2DCEE): A sustainable internal combustion engine with 60%+ brake thermal efficiency potential at 45 bar BMEP
- 2022
-
Ingår i: Energy Conversion and Management. - : Elsevier BV. - 0196-8904. ; 264
-
Tidskriftsartikel (refereegranskat)abstract
- Hydrogen (H-2) internal combustion engines may represent cost-effective and quick solution to the issue of the road transport decarbonization. A major factor limiting their competitiveness relative to fuel cells (FC) is the lower efficiency. The present work aims to demonstrate the feasibility of a H-2 engine with FC-like 60%+ brake thermal efficiency (BTE) levels using a double compression-expansion engine (DCEE) concept combined with a high pressure direct injection (HPDI) nonpremixed H-2 combustion. Experimentally validated 3D CFD simulations are combined with 1D GT-Power simulations to make the predictions. Several modifications to the system design and operating conditions are systematically implemented and their effects are investigated. Addition of a catalytic burner in the combustor exhaust, insulation of the expander, dehumidification of the EGR, and removal of the intercooling yielded 1.5, 1.3, 0.8, and 0.5%-point BTE improvements, respectively. Raising the peak pressure to 300 bar via a larger compressor further improved the BTE by 1.8%-points but should be accompanied with a higher injector-cylinder differential pressure. The lambda of ~1.4 gave the optimum tradeoff between the mechanical and combustion efficiencies. A peak BTE of 60.3% is reported with H2DCEE, which is ~5%-points higher than the best diesel-fueled DCEE alternative.
|
|
| 7. |
- Malmhall-Bah, E, et al.
(författare)
-
RHO EXPRESSION FACILITATES T CELL MIGRATION TO LYMPH NODES IN RESPONSE INFLAMMATION
- 2021
-
Ingår i: ANNALS OF THE RHEUMATIC DISEASES. - : BMJ. - 0003-4967 .- 1468-2060. ; 80, s. 12-13
-
Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- Deficiency in geranylgeranyltransferase type I (GGTase-I) results in accumulation of active Rho family proteins RhoA, Rac1 and Cdc42, responsible for cell communication and migration. We reported that mice with GGTase-I deficient macrophages (GLC mice) develop a spontaneous and age-dependent arthritis, reproducing pathology of RA [1].Objectives:We study how GGTase-I deficiency in Mø changes T cell phenotype to facilitate their translocation to joints and the development of arthritis.Methods:GLC mice were developed on a mixed genetic background (129Ola/Hsd-C57BL/6) by Cre-technology using LysM-promotor to knockout the Pggt1b gene in Mø[2]. CD4+ cells were isolated from spleen and lymph node (LN) of 16 weeks-old mice (GLC n=7, wt n=5) expected to have high prevalence of arthritis. RNA was extracted to measure expression of the Rho proteins and signature genes to characterize differences in Th-subtypes and migration abilities of CD4+ cells between GLC and wt mice. Furthermore, Illumina RNAseq analyzed the transcriptome of LN CD4+ cells. In a separate experiment we treated GLC mice with CTLA4-FP (n=12) or PBS (n=11) for 20 weeks from the age of 5 weeks. Rationale was to disrupt Mø/T cell contact to prevent arthritis. To study Rho-protein dependent phenotype in human RA, we performed RNAseq of sorted CD4+ cells of RA patients.Results:RNAseq showed that CD4+ cells in LN of GLC mice had IFN-γ dependent cytotoxic profile and upregulated numerous pro-inflammatory genes including Eomes, Cxcr3, Tigit, Tnfsf10, Il-1rl1, Stat1, Jak3, Irf7, Irf5, Ptpn13. Furthermore, the over-represented genes often depended on the IRF family in their transcription.GLC mice overexpressed Cdc42 and Rac1 in spleen CD4+ compared to wt (p=0.005 and p=0.048 resp.). Spleen GLC CD4+ cells had higher levels of α5β1 and α2β2 integrins, strongly correlating to Cdc42 (r= 0.61 p=0.0027 and r=0.50, p=0.018) and arthritis (r=0.64, p=0.0015 and r=0.69, p=0.0004). Importantly, Cdc42, Rac1, and RhoA were higher expressed in LN CD4+ compared to spleen (p=0.016, p=0.031 and p=0.016). In addition, Itgb1 coding for β1 integrin, was upregulated in GLC CD4+ cells of both spleen and LN (p=0.003 p=0.03, resp.), suggesting Rho proteins are important for migration of CD4+ cells to the joint draining LN and for arthritis development. CD4+ cells that migrated to the LN had high proportion of Foxp3+ cells. This also correlated to the expression of Itgb1 (r=0.84, p=0.0012) presenting a plausible mechanism for increased influx of Tregs into joints. Several observations are in favor of this notion. First, GLC mice expressed more Foxp3 in LN compared to spleen CD4+ cells (p=0.016). Second, transcription of Foxp3 in LN CD4+ cells was higher in GLC mice compared to wt (p=0.015). Third, this high Foxp3 coexisted with low transcription of Lef1 (p=0.03), required for Treg immunosuppression. Last, Foxp3 correlated negatively to both Lef1 (r=-0.72, p=0.017), and its cofactor Tcf1 (r=-0.75, p=0.01).CTLA4-FP reduced inflammation in GLC mice evident as lower IFN-γ, IL-6 and TNF-α production (p=0.0002, p<0.0001 and p<0.0001 resp.) and the number of CD25+CD4+cells in spleen (p=0.027). In contrast, we observed increased IL-17A production (p=0.056). However, CTLA4-FP treatment did not affect migration of CD4+ cells enriched with Rho-protein into draining LN nor alleviate arthritis.Similar to the GLC mice, CD4+ cells of RA patients with high expression of RhoA, Rac1 and Cdc42 demonstrated enrichment for Th1 signature genes including IFNG, TBX21, Eomes, IL2RA, IL2RB, IL12RB2, TNF, IL18RAP (all, adj. p<0.05).Conclusion:This study shows that accumulation of Rho-proteins in CD4+ cells results in pro-inflammatory IFN-γ dependent phenotype in mice and human RA. Accumulation of RhoA, Rac1 and Cdc42 proteins trigger the migration of CD4+ cells into joint draining LN and facilitates arthritis. Inhibiting Mø/T cell contact in GLC mice did not suffice to prevent migration of Rho-protein expressing cells and arthritisReferences:[1]Khan, O.M., et al. J Clin Invest, 2011. 121(2): p. 628-39.[2]Akula, M.K., et al. Nat Commun, 2019. 10(1): p. 3975.Disclosure of Interests:None declared
|
|
| 8. |
- Mikus, MS, et al.
(författare)
-
Plasma proteins elevated in severe asthma despite oral steroid use and unrelated to Type-2 inflammation
- 2022
-
Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 59:2
-
Tidskriftsartikel (refereegranskat)abstract
- Asthma phenotyping requires novel biomarker discovery.ObjectivesTo identify plasma biomarkers associated with asthma phenotypes by application of a new proteomic panel to samples from two well-characterised cohorts of severe (SA) and mild-to-moderate (MMA) asthmatics, COPD subjects and healthy controls (HCs).MethodsAn antibody-based array targeting 177 proteins predominantly involved in pathways relevant to inflammation, lipid metabolism, signal transduction and extracellular matrix was applied to plasma from 525 asthmatics and HCs in the U-BIOPRED cohort, and 142 subjects with asthma and COPD from the validation cohort BIOAIR. Effects of oral corticosteroids (OCS) were determined by a 2-week, placebo-controlled OCS trial in BIOAIR, and confirmed by relation to objective OCS measures in U-BIOPRED.ResultsIn U-BIOPRED, 110 proteins were significantly different, mostly elevated, in SA compared to MMA and HCs. 10 proteins were elevated in SA versus MMA in both U-BIOPRED and BIOAIR (alpha-1-antichymotrypsin, apolipoprotein-E, complement component 9, complement factor I, macrophage inflammatory protein-3, interleukin-6, sphingomyelin phosphodiesterase 3, TNF receptor superfamily member 11a, transforming growth factor-β and glutathione S-transferase). OCS treatment decreased most proteins, yet differences between SA and MMA remained following correction for OCS use. Consensus clustering of U-BIOPRED protein data yielded six clusters associated with asthma control, quality of life, blood neutrophils, high-sensitivity C-reactive protein and body mass index, but not Type-2 inflammatory biomarkers. The mast cell specific enzyme carboxypeptidase A3 was one major contributor to cluster differentiation.ConclusionsThe plasma proteomic panel revealed previously unexplored yet potentially useful Type-2-independent biomarkers and validated several proteins with established involvement in the pathophysiology of SA.
|
|
| 9. |
|
|
