| 1. |
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| 2. |
- Shabbir, Faisal, et al.
(author)
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Experimental and Numerical Investigation of Construction Defects in Reinforced Concrete Corbels
- 2023
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In: Buildings. - : MDPI. - 2075-5309. ; 13:9
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Journal article (peer-reviewed)abstract
- Reinforced concrete corbels were examined in this study for the cracking behavior and strength evaluation, focusing on defects typically found in these structures. A total of 11 corbel specimens were tested, including healthy specimens (HS), specimens with lower concrete strength (LC), specimens with less reinforcement ratio (LR), and specimens with more concrete cover than specifications (MC). The HS specimens were designed using the ACI conventional method. The specimens were tested under static loading conditions, and the actual strengths along with the crack patterns were determined. In the experimental tests, the shear capacity of the HS specimens was 28.18% and 57.95% higher than the LR and LC specimens, respectively. Similarly, the moment capacity of the HS specimens was 25% and 57.52% greater than the LR and LC specimens, respectively. However, in the case of the built-up sections, the shear capacity of the HS specimens was 9.91% and 37.51% higher than the LR and LC specimens, respectively. Likewise, the moment capacity of the HS specimens was 39.91% and 14.30% higher than the LR and LC specimens, respectively. Moreover, a detailed nonlinear finite element model (FEM) was developed using ABAQUS, and a more user-friendly strut and tie model (STM) was investigated toward its suitability to assess the strengths of the corbels with construction defects. The results from FEM and STM were compared. It was found that the FEM results were in close agreement with their experimental counterparts.
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| 3. |
- Ahmad, H R Shabbir
(author)
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Mechanism of enzymes involved in leukotriene C4 biosynthesis
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Cysteinyl leukotrienes (cys-LTs) are potent proinflammatory mediators associated with various diseases including asthma and allergic rhinitis. Leukotriene C4 synthase (LTC4S) and microsomal glutathione transferase 2 (MGST2) catalyze conjugation of the epoxide intermediate LTA4 with GSH to form LTC4, the parent compound of the cys-LTs. Both enzymes belong to the Membrane-Associated Proteins in Eicosanoid and Glutathione metabolism (MAPEG) super family of integral membrane proteins involved in the generation of lipid mediators and in the metabolism of xenobiotics. This thesis investigates the catalytic mechanism and regulation of LTC4S and MGST2. MGST2 can also catalyze conjugation of glutathione (GSH) with electrophilic substrates, such as 1-chloro-2,4-dinitrobenzene (CDNB) and also possesses GSH-dependent peroxidase activity. In this thesis, the overall catalytic mechanism and substrate specificity of human MGST2 has been characterized using purified enzyme. MGST2 (kcat/KmLTA4 = 1.8 × 104 M-1 s-1) was found to be about 50 times less efficient in catalyzing the biosynthesis of LTC4 compared to LTC4S (kcat/KmLTA4 = 8.7 × 105 M-1 s-1), while the KmLTA4 for MGST2 (40 µM) and LTC4S (30 µM) were in a similar range. A comparison of LTC4S activity with other GSTs suggests that MGST2 could catalyze conjugation of LTA4 with GSH to form LTC4 under physiological conditions. Both LTC4S and MGST2 bind GSH and activate it to form thiolate anion (GS-) at physiological pH and the pKa of enzyme bound GSH was found to be 5.9 and 6.3, respectively. The mechanism of GS- formation was characterized for both enzymes using pre-steady-state kinetics. The amplitude analysis of the signals from all different kinetic and spectroscopic experiments suggested that the GS- / enzyme subunit stoichiometry was 3/3 for LTC4S and 1/3 for MGST2, which may partly explain the difference in catalytic efficiency. To conclusively show that MGST2 is a functional homo-trimer with one-third-of-the-sites reactivity we combined the results from blue native PAGE, differential scanning calorimetry, isothermal titration calorimetry and equilibrium dialysis followed by global kinetic simulations. Analysis of all microscopic rates and equilibrium constants for GSH binding and activation suggest that GS- formation is not a rate-limiting factor for LTC4S, as has been observed for other MAPEG members, such as MGST1. Conversely, GS- formation (k2 = 41.1 s-1) was faster for MGST2 relative to MGST1, but within only one site of the homo-trimer at a given time. Furthermore, pre-steady-state kinetics using CDNB as an electrophilic substrate showed that the chemical conjugation step is most likely rate limiting for MGST2 catalysis under physiological conditions. Recently, a ribosomal S6 kinase (p70S6k) was shown to play a role in the phosphoregulation of LTC4S in monocytes. Here, we identified a major p70S6k phosphorylation site on LTC4S as Ser-36, along with a low-frequency site at Thr-40, by an in vitro phosphorylation assay followed by mass spectrometric analysis. Phosphomimetic mutants were generated to study the functional consequences of phosphorylation by kinetic analysis, molecular dynamics simulations and structural studies. Our results identified Ser-36 as the functionally important site for the regulation of LTC4S activity, where phosphorylation impairs catalytic activity via a mechanism of hydrogen bonding interactions between the phosphoserine and the catalytically important Arg-104, as well as by limiting substrate access to the active site. In summary, MGST2 displays broad substrate specificity similar to MGST1, whereas LTC4S is highly specific towards LTA4 as a physiological substrate. The distinct catalytic and mechanistic properties of MGST2 and LTC4S suggest that while the former may fulfill a promiscuous role in several biochemical pathways, the latter has evolved to fulfill a specific physiological function of LTC4 synthesis. In general, the acquired knowledge about the LTC4S and MGST2 will be useful for the development of pharmaceuticals against inflammatory diseases, and in addition, will provide context during the physiological and mechanistic characterization of other MAPEG members. Moreover, the observed regulation of LTC4S activity through phosphorylation is unique among the MAPEG members and the results presented herein will provide important clues for understanding the mechanism of phosphoregulation during cys-LT biosynthesis.
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| 4. |
- Ahmad, Shabbir, et al.
(author)
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Trimeric microsomal glutathione transferase 2 displays one third of the sites reactivity
- 2015
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In: Biochimica et Biophysica Acta - Proteins and Proteomics. - : Elsevier BV. - 1570-9639 .- 1878-1454. ; 1854:1010 Pt A, s. 1365-1371
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Journal article (peer-reviewed)abstract
- Human microsomal glutathione transferase 2 (MGST2) is a trimeric integral membrane protein that belongs to the membrane-associated proteins in eicosanoid and glutathione metabolism (MAPEG) family. The mammalian MAPEG family consists of six members where four have been structurally determined. MGST2 activates glutathione to form a thiolate that is crucial for GSH peroxidase activity and GSH conjugation reactions with electrophilic substrates, such as 1-chloro-2,4-dinitrobenzene (CDNB). Several studies have shown that MGST2 is able to catalyze a GSH conjugation reaction with the epoxide LTA(4) forming the pro-inflammatory LTC4. Unlike its closest homologue leukotriene C-4 synthase (LTC4S), MGST2 appears to activate its substrate GSH using only one of the three potential active sites [Ahmad S, et al. (2013) Biochemistry. 52, 1755-1764]. In order to demonstrate and detail the mechanism of one-third of the sites reactivity of MGST2, we have determined the enzyme oligomeric state, by Blue native PAGE and Differential Scanning Calorimetry, as well as the stoichiometty of substrate and substrate analog inhibitor binding to MGST2, using equilibrium dialysis and Isothermal Titration Calorimetry, respectively. Global simulations were used to fit kinetic data to determine the catalytic mechanism of MGST2 with GSH and CDNB (1-chloro-2,4-dinitrobenzene) as substrates. The best fit was observed with 1/3 of the sites catalysis as compared with a simulation where all three sites were active. In contrast to LTC4S, MGST2 displays a 1/3 the sites reactivity, a mechanism shared with the more distant family member MGST1 and recently suggested also for microsomal prostaglandin E synthase-1.
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| 5. |
- Ans, Muhammad, et al.
(author)
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Designing Three‐dimensional (3D) Non‐Fullerene Small Molecule Acceptors with Efficient Photovoltaic Parameters
- 2018
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In: ChemistrySelect. - : WILEY-VCH VERLAG GMBH. - 2365-6549. ; 3:45, s. 12797-12804
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Journal article (peer-reviewed)abstract
- Three dimensional (3D) acceptor‐donor‐acceptor (A−D‐A) type small molecules (M1, M2, M3 and M4) are theoretically investigated for optoelectronic properties. The designed molecules contain spirobifluorene as core unit linked with end capped acceptors through four four thieno‐[3,2‐b]Thiophene (TT) units. The end capped acceptors are (3‐methyl‐2‐thioxothiazolidin‐4‐one) (M1), 2‐(2‐ethylidene‐5,6‐difluoro‐3‐oxo‐2,3‐dihydroinden‐1‐ylidene)malononitrile (M2), 2‐(3‐ethyl‐4‐oxothiazolidin‐2‐ylidine)malononitrile (M3) and 2‐(2‐ethylidene‐5,6‐dicyano‐3‐oxo‐2,3‐dihydroinden‐1‐ylidene)malononitrile (M4). The photovoltaic parameters of the designed molecules are compared with the recently reported reference compound R. Among all designed molecules, M4 is a low energy gap material (2.28 eV), broad absorption which is attributed to excellent communication between strong electron withdrawing end capped acceptors through extended conjugation. All newly designed molecules have lower binding energy as compared to reference molecule R which results in higher exciton dissociation in excited state. The reorganization energy calculations indicate good charge transfer ability of the designed molecules. M4 shows the lowest λe (0.0022) value with respect to the reference molecule R (0.034) which signifies its enhanced electronic transport behavior. The calculated open circuit voltages (Voc) ranges from 1.97 to 2.36 eV, 2.11 to 2.49 eV and 1.9 eV to 2.28 eV with respect to three different well known donor materials PTB7‐Th, PBDB−T and P3HT, respectively.
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| 6. |
- Bibi, Uzma, et al.
(author)
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Graphene-Based Strain Sensing of Cementitious Composites with Natural and Recycled Sands
- 2023
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In: Sensors. - : MDPI. - 1424-8220. ; 23:16
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Journal article (peer-reviewed)abstract
- Structural health monitoring is crucial for ensuring the safety and reliability of civil infrastructures. Traditional monitoring methods involve installing sensors across large regions, which can be costly and ineffective due to the sensors damage and poor compliance with structural members. This study involves systematically varying the graphene nanoplatelets (GNPs) concentration and analyzing the strength performance and piezoresistive behavior of the resulting composites. Two different composites having natural and recycled sands with varying percentages of GNPs as 2%, 4%, 6%, and 8% were prepared. Dispersion of GNPs was performed in superplasticizer and then ultrasonication was employed by using an ultrasonicator. The four-probe method was utilized to establish the piezoresistive behavior. The results revealed that the compressive strength of mortar cubes with natural sand was increased up to a GNP content of 6%, beyond which it started to decline. In contrast, specimens with recycled sand showed a continuous decrease in the compressive strength. Furthermore, the electrical resistance stability was observed at 4% for both natural and recycled sands specimens, exhibiting linearity between the frictional change in the resistivity and compressive strain values. It can be concluded from this study that the use of self-sensing sustainable cementitious composites could pave their way in civil infrastructures.
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| 7. |
- Ehsan, Muhsan, et al.
(author)
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Groundwater delineation for sustainable improvement and development aided by GIS, AHP, and MIF techniques
- 2024
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In: Applied water science. - : Springer Science and Business Media Deutschland GmbH. - 2190-5487 .- 2190-5495. ; 14:2
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Journal article (peer-reviewed)abstract
- Exploration of groundwater is an integral part of viable resource growth for society, economy, and irrigation. However, uncontrolled utilization is mainly reported in urban and industries due to the increasing demand for water in semi-arid and arid regions of the world. In the background, groundwater demarcation for potential areas is vital in meeting necessary demand. The current study applied an integrated method comprising the analytical hierarchy process (AHP), multiple influence factors (MIF), combined with a linear regression curve and observatory well data for groundwater prospects mapping. Thematic maps such as flow direction, flow accumulation, elevation map, land use land cover, slope, soil texture, hill shade, geomorphology, normalized vegetation index, and groundwater depth map were generated utilizing remote sensing techniques. The relative weight of each parameter was estimated and then assigned to major and minor parameters. Potential zones for groundwater were classified into five classes, namely very good, good, moderate, poor, and very poor, based on AHP and MIF methods. A spatially explicit sensitivity and uncertainty analysis method to a GIS-based multi-criteria groundwater potential zone model is presented in this research. The study addressed a flaw in the way groundwater potential mapping results are typically presented in GIS-based multi-criteria decision analysis studies, where discrete class outputs are used without any assessment of their certainty with respect to variations in criteria weighting, which is one of the main contributors to output uncertainty. The study region is categorized based on inferred results as very poor, poor, marginal, and very good in potential ground quality 3.04 km2 is considered extremely poor, 3.33 km2 is considered poor, 64.42 km2 is considered very good, and 85.84 km2 is considered marginal zones, which shows reliable and potential implementation. The outcomes of AHP and MIF were validated by linear regression curve and actual water table in a study area. The study results help to formulate the potential demarcation of groundwater zones for future sustainable planning and development of groundwater sources. This study may be helpful to provide a cost-effective solution to water resources crises. The current study finding may be helpful for decision-makers and administrative professionals for sustainable management of groundwater resources for present and future demands.
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| 8. |
- Koomson, Isaac, et al.
(author)
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Non-farm entrepreneurship, caste, and energy poverty in rural India
- 2023
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In: Energy Economics. - 0140-9883 .- 1873-6181. ; 127
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Journal article (peer-reviewed)abstract
- This study examines how non-farm entrepreneurship influences rural household energy poverty and explores caste-based heterogeneities in outcomes in India. The study used different quasi-experimental econometric methods to analyse panel data from the waves 1 and 2 (2015 and 2018) of the Access to Clean Cooking Energy and Electricity Survey of States (ACCESS) in India. The overall results across all estimation methods show that households' engagement in non-fam entrepreneurship significantly contributes to a reduction in their energy poverty levels and the probability of being energy poor. The sizes of the reduction vary across the four castes (General Caste, Scheduled Tribe, Scheduled Caste, and Other Backward Caste). The energy poverty reducing effect of non-farm entrepreneurship is particularly high among members of the Scheduled Tribe. Further mediation analyses reveal that non-farm entrepreneurship potentially affects rural households' energy poverty through their accumulation of financial (savings) and durable assets which possibly enable them to access cleaner energy sources for lighting and cooking. We encourage governments to pay attention to policies that promote non-farm entrepreneurship which has the potential to enhance asset accumulation and reduce rural energy poverty in the process.
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| 9. |
- Lindberg, Diana, 1970-, et al.
(author)
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Mutations in salt-bridging residues at the interface of the core and lid domains of epoxide hydrolase StEH1 affect regioselectivity, protein stability and hysteresis
- 2010
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In: Archives of Biochemistry and Biophysics. - Amsterdam : Elsevier. - 0003-9861 .- 1096-0384. ; 495:2, s. 165-173
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Journal article (peer-reviewed)abstract
- Epoxide hydrolase, StEH1, shows hysteretic behavior in the catalyzed hydrolysis of trans-2-methylstyrene oxide (2-MeSO)(1). Linkage between protein structure dynamics and catalytic function was probed in mutant enzymes in which surface-located salt-bridging residues were substituted. Salt-bridges at the interface of the alpha/beta-hydrolase fold core and lid domains, as well as between residues in the lid domain, between Lys(179)Asp(202), Glu(215)-Arg(41) and Arg(236)-Glu(136) were disrupted by mutations, K179Q E215Q, R236Q and R236Q. All mutants displayed enzyme activity with styrene oxide (SO) and 2-MeSO when assayed at 30 degrees C. Disruption of salt-bridges altered the rates for isomerization between distinct Michaelis complexes, with (1R,2R)-2-MeSO as substrate, presumably as a result of increased dynamics of involved protein segments. Another indication of increased flexibility was a lowered thermostability in all mutants. We propose that the alterations to regioselectivity in these mutants derive from an increased mobility in protein segments otherwise stabilized by salt bridging interactions.
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| 10. |
- Lu, Lu, 1984-, et al.
(author)
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Synthesis and in vitro biological evaluation of quinolinyl pyrimidines targeting type II NADH-dehydrogenase (NDH-2)
- 2022
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In: ACS - Infectious Diseases. - : American Chemical Society (ACS). - 2373-8227. ; 8:3, s. 482-498
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Journal article (peer-reviewed)abstract
- Type II NADH dehydrogenase (NDH-2) is an essential component of electron transfer in many microbial pathogens but has remained largely unexplored as a potential drug target. Previously, quinolinyl pyrimidines were shown to inhibit Mycobacterium tuberculosis NDH-2, as well as the growth of the bacteria [Shirude, P. S.; ACS Med. Chem. Lett. 2012, 3, 736−740]. Here, we synthesized a number of novel quinolinyl pyrimidines and investigated their properties. In terms of inhibition of the NDH-2 enzymes from M. tuberculosis and Mycobacterium smegmatis, the best compounds were of similar potency to previously reported inhibitors of the same class (half-maximal inhibitory concentration (IC50) values in the low-μM range). However, a number of the compounds had much better activity against Gram-negative pathogens, with minimum inhibitory concentrations (MICs) as low as 2 μg/mL. Multivariate analyses (partial least-squares (PLS) and principle component analysis (PCA)) showed that overall ligand charge was one of the most important factors in determining antibacterial activity, with patterns that varied depending on the particular bacterial species. In some cases (e.g., mycobacteria), there was a clear correlation between the IC50 values and the observed MICs, while in other instances, no such correlation was evident. When tested against a panel of protozoan parasites, the compounds failed to show activity that was not linked to cytotoxicity. Further, a strong correlation between hydrophobicity (estimated as clog P) and cytotoxicity was revealed; more hydrophobic analogues were more cytotoxic. By contrast, antibacterial MIC values and cytotoxicity were not well correlated, suggesting that the quinolinyl pyrimidines can be optimized further as antimicrobial agents.
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