Efficacy of Various Implant Abutment Screw Access Channel Sealing Materials in Preventing Microleakage: A Systematic Review

The aim of this systematic review is to evaluate the effectiveness of different materials used for sealing dental implant abutment screw access channel (ASAC), in preventing microleakage. As per the searched indexed English literature, this study is the first review of its kind. Indexed English literature published up to 20 th February 2021 was systematically searched on relevant electronic data bases. The recommendations specified by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) were applied for constructing framework, and reporting the current review. The focused PICO question was: “Which material (C) is more effective in sealing (I) implant ASAC (P) in terms of causing minimal microbial leakage (O)”. Quality of articles was assessed with modified CONSORT scale for in vitro studies. Five in vitro studies were selected for qualitative analysis after final stage screening. Modified CONSORT scale suggested that out of the five selected studies, one each was of low and high quality, whereas three studies were of moderate quality. Included studies had contrasting results related to the efficacy these materials as sealants in ASAC. Sealing capacity against microleakage should be considered as one of the important criteria while selecting the material to fill implant ASAC. Definitive conclusions asserting superiority of a single material over others are difficult to draw, due to non-homogeneity in study design of the included papers. More studies should be conducted in the near future to investigate the efficacy of various combination of materials in preventing micro leakage.

Structure and functionality of a multimeric human COQ7:COQ9 complex

Coenzyme Q (CoQ, ubiquinone) is a redox-active lipid essential for core metabolic pathways and antioxidant defense. CoQ is synthesized upon the mitochondrial inner membrane by an ill-defined 'complex Q' metabolon. Here we present a structure and functional analyses of a substrate- and NADH-bound oligomeric complex comprised of two complex Q subunits: the hydroxylase COQ7, which performs the penultimate step in CoQ biosynthesis, and the prenyl lipid-binding protein COQ9. We reveal that COQ7 adopts a modified ferritin-like fold with an extended hydrophobic access channel whose substrate binding capacity is enhanced by COQ9. Using molecular dynamics simulations, we further show that two COQ7:COQ9 heterodimers form a curved tetramer that deforms the membrane, potentially opening a pathway for CoQ intermediates to translocate from within the bilayer to the proteins' lipid-binding sites. Two such tetramers assemble into a soluble octamer, closed like a capsid, with lipids captured within. Together, these observations indicate that COQ7 and COQ9 cooperate to access hydrophobic precursors and coordinate subsequent synthesis steps toward producing mature CoQ.

Sliding Group Window with Rebacking off for Collision Avoidance in High-Efficiency Wireless Networks

It is difficult for wireless local area networks (WLANs), IEEE 802.11ax high-efficiency WLAN (HEW), to join next-generation innovations such as 5th generation (5G) and Internet of Things (IoT) because they still have their conventional channel access mechanism as their essential medium access control (MAC) protocol. The MAC protocol uses a traditional binary exponential backoff (BEB) algorithm to access channel resources that depend on the noncognitive increment of contention parameters for collision avoidance. In BEB, the collision issue increases with the increase in connected devices in the network due to a fixed contention window size. The larger the size of the network, the larger the collision in the network. To avoid such a circumstance, in this paper, we propose a sliding group window (sGW) mechanism dependent on collision-point assessment in order to improve the performance of MAC protocol for HEW. The proposed algorithm additionally presents a rebacking off for collision avoidance (ReBOCA) system for sGW, which combines the uniform dispersion of the contention parameters. This variation of an ordinary backoff algorithm permits the reasonable sliding of the user groups in the case of collision. The algorithm explicitly accounts for the peculiarities of dense environments and backward compatibility. Key aspects of the proposed solution include collision-point estimation, rebacking off for collision distribution convergence for fair treatment, and adaptive sliding of group windows to mitigate contention unfairness. We further formulated a closed-form Markov chain model for the performance analysis of our proposed sGW with ReBOCA scheme. Theoretical and practical results prove that our proposed scheme achieved maximal efficiency, even under dense environments. An increase in throughput with a lower packet collision probability was achieved with the proposed mechanism, and the efficiency increased as the number of contending stations increased than compared to traditional BEB performance. Our proposed ReBOCA mechanism enhanced network throughput by 38.18% than compared to the conventional BEB mechanism.

Insights into the Genetic Variations of Human Cytochrome P450 2C9: Structural Analysis, Characterization and Comparison

Cytochromes P450 (CYP) are one of the major xenobiotic metabolizing enzymes with increasing importance in pharmacogenetics. The CYP2C9 enzyme is responsible for the metabolism of a wide range of clinical drugs. More than sixty genetic variations have been identified in CYP2C9 with many demonstrating reduced activity compared to the wild-type (WT) enzyme. The CYP2C9*8 allele is predominantly found in persons of African ancestry and results in altered clearance of several drug substrates of CYP2C9. The X-ray crystal structure of CYP2C9*8, which represents an amino acid variation from arginine to histidine at position 150 (R150H), was solved in complex with losartan. The overall conformation of the CYP2C9*8-losartan complex was similar to the previously solved complex with wild type (WT) protein, but it differs in the occupancy of losartan. One molecule of losartan was bound in the active site and another on the surface in an identical orientation to that observed in the WT complex. However, unlike the WT structure, the losartan in the access channel was not observed in the *8 complex. Furthermore, isothermal titration calorimetry studies illustrated weaker binding of losartan to *8 compared to WT. Interestingly, the CYP2C9*8 interaction with losartan was not as weak as the CYP2C9*3 variant, which showed up to three-fold weaker average dissociation constant compared to the WT. Taken together, the structural and solution characterization yields insights into the similarities and differences of losartan binding to CYP2C9 variants and provides a useful framework for probing the role of amino acid substitution and substrate dependent activity.

Controlling the Substrate Specificity of an Enzyme through Structural Flexibility by Varying the Salt-Bridge Density

Many enzymes, particularly in one single family, with highly conserved structures and folds exhibit rather distinct substrate specificities. The underlying mechanism remains elusive, the resolution of which is of great importance for biochemistry, biophysics, and bioengineering. Here, we performed a neutron scattering experiment and molecular dynamics (MD) simulations on two structurally similar CYP450 proteins; CYP101 primarily catalyzes one type of ligands, then CYP2C9 can catalyze a large range of substrates. We demonstrated that it is the high density of salt bridges in CYP101 that reduces its structural flexibility, which controls the ligand access channel and the fluctuation of the catalytic pocket, thus restricting its selection on substrates. Moreover, we performed MD simulations on 146 different kinds of CYP450 proteins, spanning distinct biological categories including Fungi, Archaea, Bacteria, Protista, Animalia, and Plantae, and found the above mechanism generally valid. We demonstrated that, by fine changes of chemistry (salt-bridge density), the CYP450 superfamily can vary the structural flexibility of its member proteins among different biological categories, and thus differentiate their substrate specificities to meet the specific biological needs. As this mechanism is well-controllable and easy to be implemented, we expect it to be generally applicable in future enzymatic engineering to develop proteins of desired substrate specificities.

Deciphering Structural Alterations Associated with Activity Reductions of Genetic Polymorphisms in Cytochrome P450 2A6 Using Molecular Dynamics Simulations

Cytochrome P450 (CYP) 2A6 is a monooxygenase involved in the metabolism of various endogenous and exogenous chemicals, such as nicotine and therapeutic drugs. The genetic polymorphisms in CYP2A6 are a cause of individual variation in smoking behavior and drug toxicities. The enzymatic activities of the allelic variants of CYP2A6 were analyzed in previous studies. However, the three-dimensional structures of the mutants were not investigated, and the mechanisms underlying activity reduction remain unknown. In this study, to investigate the structural changes involved in the reduction in enzymatic activities, we performed molecular dynamics simulations for ten allelic mutants of CYP2A6. For the calculated wild type structure, no significant structural changes were observed in comparison with the experimental structure. On the other hand, the mutations affected the interaction with heme, substrates, and the redox partner. In CYP2A6.44, a structural change in the substrate access channel was also observed. Those structural effects could explain the alteration of enzymatic activity caused by the mutations. The results of simulations provide useful information regarding the relationship between genotype and phenotype.