Low density lipoprotein catabolism is enhanced by the cleaved form of alpha-1-antitrypsin

The frequent occurrence of hypocholesterolaemia following inflammatory processes is well known but unexplained. Elevated plasma levels of serine proteinase inhibitors (serpins) and their complexes with target enzymes have been demonstrated in inflammatory, malignant and infectious diseases which are also often accompanied by low plasma cholesterol levels. Under inflammatory conditions, uncomplexed, but cleaved inactive serpins arising from slow deacylation of the serpin-proteinase complex may be present in the circulation. To determine the influence of native and cleaved forms of serpins, such as alpha-1-antitrypsin (AAT), on lipoprotein metabolism, we investigated the effect of these forms on low density lipoprotein (LDL) catabolism in human HepG2 cell line. We have found that the cleaved form of AAT in concentrations from 125 to 2000 nmol l-1 stimulates LDL binding to the HepG2 cells, by up to 49% with a subsequent increase in LDL uptake and degradation of up to 79 and 65% respectively. Native AAT was also found to increase LDL binding and internalization by 20-25%, independently of the amount of AAT added, an effect most probably due to the cleaved form of AAT produced by local proteolysis of native AAT incubated in the cell culture. Moreover we have shown that the cleaved form of AAT interacts with LDL in vitro, and that such an interaction abolishes AAT ability to stimulate LDL binding and internalization. This study for the first time describes the ability of the cleaved form of AAT to stimulate LDL binding and internalization in HepG2 cell culture, and provides evidence that hypocholesterolaemia occurring during inflammatory processes may be mediated by cleaved forms of serpins.     

Lower limb contribution in kayak performance: modelling,simulation and analysis

Lower limb contribution in flatwater kayaking is difficult to quantify experimentally because lower-limbs and pelvis are hidden in the kayak. A computer simulation model was developed to assess the lower limb contribution to kayak performance. Three simulated movements were compared in terms of paddle tip velocity, force impulse, and mechanical work. The pelvis motion increased the paddle tip velocity by 0.15 m s⁻¹ at the stroke beginning and 0.34 m s⁻¹ afterward. The propulsive impulse was also modified by pelvis rotation with a 3.5 N s increase per stroke. For a set performance, the co-ordination involving the lower limbs decreased the mechanical work by 20 J. The above results were obtained by modelling the Ergometer-Athlete-Paddle {EAP} system using 18 bodies and 31 degrees of freedom. The motion capture data were transformed in generalized coordinate time histories by solving an inverse kinematics problem with optimization in order to assess both lower limb and upper limb positions and produce a cyclic motion. Then the {EAP} was simulated based on Lagrangian dynamics with Lagrange multipliers to introduce the paddle forces. Finally, the joint torques were calculated by solving an inverse dynamics problem with optimization in order to ensure a good distribution of lower limbs actuating torques.     

Estimating joint kinematics of a whole body chain model with closed-loop constraints

Computer simulation and optimal control requiring actual joint kinematics and based on the definition of a chain model become more used in biomechanics for studying the musculo-skeletal coordination or optimizing the performance. For this purpose, numerical optimization methods using a chain model have been developed and showed promising results to estimate joint kinematics for open-loop movements. The aim of this study was to exhaustively compare the type of method and closed-loop constraint with four criteria: (i) reconstruction quality, (ii) loop closure respect, (iii) regularity of joint kinematics, and (iv) computational time. Five algorithms were tested to estimate the whole body joint kinematics of 10 elite athletes paddling an ergometer: global optimization (GO) without closed-loop constraints, with soft closed-loop constraints and with strict closed-loop constraints, and Kalman filter (KF) without closed-loop constraints and with soft closed-loop constraints. Each athlete was modelled using a personalized 17-segment 42-degree of freedom chain model. Input data were measured by a 10-camera motion capture system sampled at 250 Hz. ANOVAs were performed on the four criteria to identify differences between the five algorithms. Marker residuals were slightly increased by about 2–3 mm using GO under strict constraints and KF with soft constraints. Closed-loop errors were five times reduced when introducing constraints (10 to 2 mm). KF algorithms gave significantly smoother joint kinematics than the three GO algorithms. Computational time was largely increased by introducing closed-loop constraints in GO algorithm (from 21 to 200 ms per frame) while it remained unchanged in KF algorithm (about 60 ms per frame). To conclude, KF with soft constraints represents the best compromise between the four criteria.     

Composition of negative air ions as a function of ion age and selected trace gases: Mass- and mobility distribution

In order to explore an additional window to look into the mechanisms behind atmospheric ion and particle formation, an advanced method, which combines the study of ageing of air ions by both mobility and mass spectrometry is developed and examined. The technique behind this method can produce new air ions and trace their evolution within the age interval from a few tenths of a second up to about 20 s. We measure the mobility spectra from 2.37 down to 0.0013 cm² V^?1 s^?1 and the mass spectra of these ions up to m/z 2000. The results demonstrate the ability of the method to trace the temporal evolution of the ions. The composition of negative air ions at an age of about 1 s is clearly different from that at about 20 s, contrarily to certain former results according to which the small ion evolution should mainly terminate within about a second. We investigate how variations in humidity and the elevated concentrations of iodine and diethylamine (DEA) modify the composition of the negative air ions. The concentrations of DEA and iodine are above their common values in the air, but also in these cases the observed trends should be applicable to the atmosphere. All the vapours investigated in this study modify the ion composition in quite a specific way. Most prominent transformations are induced by iodine, which transforms the mass spectrum of cluster ions into few dominant peaks at m/z 381 and 635. In mobility spectrum, it generates a large number of new heavy ions with the sizes of 4?40 nm, the heavy ions in turn decrease the concentration of cluster ions due to ion–aerosol attachment. The peaks at m/z 381 and 635 can be assigned to ions I^?(I₂) and I^?(I₂)₂, respectively. At an enhanced concentration of diethylamine vapour (DEA), the new ions NO₃^?(HNO₃)(DEA) seem very plausible to explain the appearance of the peak at m/z 198 in the mass-spectrum. DEA evokes a multimodal mobility spectrum with modes at about 1.75, 10 and 20 nm. Both the DEA and iodine generate the changes in the size distribution of aerosol particles, which can be associated with a new particle formation. The experiments with enhanced water vapour concentrations revealed a new peak at m/z 250, which could be assigned to HCO₃^?(HNO₃)₃ ions.     

Bias dependent NO2 sensitivity of SnO2 thin films at room temperature

Amorphous granular SnO₂ thin films were investigated from a standpoint of an NO₂ gas sensor working at room temperature. The films were deposited using pulsed laser deposition method with substrate at room temperature and ～90 nm thick SnO₂ films with amorphous structure were obtained as a result. SnO₂ films deposited on Pt electrode substrates formed a sensor structure that showed response I_air/I_gas to 4 ppm NO₂ up to ～8000. I–V characteristics of the sensor structure were described by the power law dependence, whereas the power indexes were different for measurements in pure air and in the presence of NO₂. As a result, the sensor response was highly dependent on bias voltage between the sensor electrodes. It was demonstrated that the nonlinear electrical characteristics and bias dependent gas sensitivity were the inherent properties of thin films and the contacts were ohmic.     

Measurements of magnesium in mononuclear cells

In this study analysis of magnesium in mononuclear cells was compared to that in muscle in patients and healthy controls. Mononuclear cell concentrations of magnesium expressed as nmol/mg cell protein correlated significantly with muscle biopsy concentrations of magnesium (r = 0,68; p less than 0,001). Hence, we suggest that analyzing of magnesium in mononuclear cells could be an easy and convenient way to estimate tissue magnesium.     

Performance-Based Design Approach in Seismic Analysis of Bridges

The seismic design requirements used in the United States are based on the recommendations of the American Association of State Highway and Transportation Officials. These requirements are primarily based on the importance of the structure, the level of deformation imposed on the structure, soil conditions, and the ductility of structural members, especially piers and supports. In the performance-based design approach, the design is primarily focused on meeting a performance objective, which is in line with a desired level of service. Currently, the effort toward implementing the performance-based design approach in buildings is under way in the United States. The seismic performance criteria for buildings have been established and reported by various organizations. It seems that at least three levels of performance, ranging from “fully operational” to “near collapse” can be used to meet the postearthquake conditions, safety, usage, and occupancy for the varous levels of service expected from all types of structures. In this paper a critical evaluation of these performance criteria and their relevance to highway bridge design, in conjunction with the current design practice, is discussed. Various types of designs such as those based on strength, deformation, nonlinear behavior, and energy, which can be used to meet the specified performance levels in seismic design of highway bridges, are also discussed in the paper. Examples of real applications of the method in highway bridges are reviewed. Furthermore, the procedure by which the performance-based method has been implemented in these example cases is described and discussed in the paper.     

Human TRMT112-Methyltransferase Network Consists of Seven Partners Interacting with a Common Co-Factor

Methylation is an essential epigenetic modification mainly catalysed by S-Adenosyl methionine-dependent methyltransferases (MTases). Several MTases require a cofactor for their metabolic stability and enzymatic activity. TRMT112 is a small evolutionary conserved protein that acts as a co-factor and activator for different MTases involved in rRNA, tRNA and protein methylation. Using a SILAC screen, we pulled down seven methyltransferases—N6AMT1, WBSCR22, METTL5, ALKBH8, THUMPD2, THUMPD3 and TRMT11—as interaction partners of TRMT112. We showed that TRMT112 stabilises all seven MTases in cells. TRMT112 and MTases exhibit a strong mutual feedback loop when expressed together in cells. TRMT112 interacts with its partners in a similar way; however, single amino acid mutations on the surface of TRMT112 reveal several differences as well. In summary, mammalian TRMT112 can be considered as a central “hub” protein that regulates the activity of at least seven methyltransferases.     

Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.     

Evaluation of head response to ballistic helmet impacts using the finite element method

Injuries to the head caused by ballistic impacts are not well understood. Ballistic helmets provide good protection, but still, injuries to both the skull and brain occur. Today there is a lack of relevant test procedure to evaluate the efficiency of a ballistic helmet. The purpose of this project was (1) to study how different helmet shell stiffness affects the load levels in the human head during an impact, and (2) to study how different impact angles affects the load levels in the human head. A detailed finite element (FE) model of the human head, in combination with an FE model of a ballistic helmet (the US Personal Armour System Ground Troops’ (PASGT) geometry) was used. The head model has previously been validated against several impact tests on cadavers. The helmet model was validated against data from shooting tests. Focus was aimed on getting a realistic response of the coupling between the helmet and the head and not on modeling the helmet in detail. The studied data from the FE simulations were stress in the cranial bone, strain in the brain tissue, pressure in the brain, change in rotational velocity and translational and rotational acceleration. A parametric study was performed to see the influence of a variation in helmet shell stiffness on the outputs from the model. The effect of different impact angles was also studied. Dynamic helmet shell deflections larger than the initial distance between the shell and the skull should be avoided in order to protect the head from the most injurious threat levels. It is more likely that a fracture of the skull bone occurs if the inside of the helmet shell strikes the skull. Oblique ballistic impacts may in some cases cause higher strains in the brain tissue than pure radial ones.