Mechanism of attenuation of muscle protein degradation induced by tumor necrosis factor-alpha and angiotensin II by beta-hydroxy-beta-methylbutyrate

Both tumor necrosis factor-alpha (TNF-alpha)/interferon-gamma (IFN-gamma) and angiotensin II (ANG II) induced an increase in total protein degradation in murine myotubes, which was completely attenuated by treatment with beta-hydroxy-beta-methylbutyrate (HMB; 50 microM). There was an increase in formation of reactive oxygen species (ROS) within 30 min, as well as an increase in the activity of both caspase-3 and -8, and both effects were attenuated by HMB. Moreover, inhibitors of caspase-3 and -8 completely attenuated both ROS formation and total protein degradation induced by TNF-alpha/IFN-gamma and ANG II. There was an increased autophosphorylation of double-stranded RNA-dependent protein kinase (PKR), which was attenuated by the specific caspase-3 and -8 inhibitors. Neither ROS formation or protein degradation occurred in myotubes expressing a catalytically inactive PKR variant, PKRDelta6, in response to TNF-alpha/IFN-gamma, compared with myotubes expressing wild-type PKR, although there was still activation of caspase-3 and -8. HMB also attenuated activation of PKR, suggesting that it was important in protein degradation. Formation of ROS was attenuated by rotenone, an inhibitor of the mitochondrial electron transport chain, nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, and SB 203580, a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), which also attenuated total protein degradation. Activation of p38 MAPK by PKR provides the link to ROS formation. These results suggest that TNF-alpha/IFN-gamma and ANG II induce muscle protein degradation by a common signaling pathway, which is attenuated by HMB, and that this involves the initial activation of caspase-3 and -8, followed by autophosphorylation and activation of PKR, which then leads to increased ROS formation via activation of p38 MAPK. Increased ROS formation is known to induce protein degradation through the ubiquitin-proteasome pathway.

Suppression pathways saturate with contrast for parallel surrounds but not for superimposed cross-oriented masks

Contrast masking from parallel grating surrounds (doughnuts) and superimposed orthogonal masks have different characteristics. However, it is not known whether the saturation of the underlying suppression that has been found for parallel doughnut masks depends on (i) relative mask and target orientation, (ii) stimulus eccentricity or (iii) surround suppression. We measured contrast-masking functions for target patches of grating in the fovea and in the periphery for cross-oriented superimposed and doughnut masks and parallel doughnut masks. When suppression was evident, the factor that determined whether it accelerated or saturated was whether the mask stimulus was crossed or parallel. There are at least two interpretations of the asymptotic behaviour of the parallel surround mask. (1) Suppression arises from pathways that saturate with (mask) contrast. (2) The target is processed by a mechanism that is subject to surround suppression at low target contrasts, but a less sensitive mechanism that is immune from surround suppression ‘breaks through’ at higher target contrasts. If the mask can be made less potent, then masking functions should shift downwards, and sideways for the two accounts, respectively. We manipulated the potency of the mask by varying the size of the hole in a parallel doughnut mask. The results provided strong evidence for the first account but not the second. On the view that response compression becomes more severe progressing up the visual pathway, our results suggest that superimposed cross-orientation suppression precedes orientation tuned surround suppression. These results also reveal a previously unrecognized similarity between surround suppression and crowding (Pelli, Palomares, & Majaj, 2004).

Kineto-elastodynamic analysis of high-speed four-bar mechanism

This thesis addresses the kineto-elastodynamic analysis of a four-bar mechanism running at high-speed where all links are assumed to be flexible. First, the mechanism, at static configurations, is considered as structure. Two methods are used to model the system, namely the finite element method (FEM) and the dynamic stiffness method. The natural frequencies and mode shapes at different positions from both methods are calculated and compared. The FEM is used to model the mechanism running at high-speed. The governing equations of motion are derived using Hamilton's principle. The equations obtained are a set of stiff ordinary differential equations with periodic coefficients. A model is developed whereby the FEM and the dynamic stiffness method are used conjointly to provide high-precision results with only one element per link. The principal concern of the mechanism designer is the behaviour of the mechanism at steady-state. Few algorithms have been developed to deliver the steady-state solution without resorting to costly time marching simulation. In this study two algorithms are developed to overcome the limitations of the existing algorithms. The superiority of the new algorithms is demonstrated. The notion of critical speeds is clarified and a distinction is drawn between "critical speeds", where stresses are at a local maximum, and "unstable bands" where the mechanism deflections will grow boundlessly. Floquet theory is used to assess the stability of the system. A simple method to locate the critical speeds is derived. It is shown that the critical speeds of the mechanism coincide with the local maxima of the eigenvalues of the transition matrix with respect to the rotational speed of the mechanism.

Understanding the link between transglutaminase and the induction of fibrosis in cystic fibrosis (CF)

The emerging role of the multifunctional enzyme, Transglutaminase 2 (TG2) in Cystic Fibrosis (CF) has been linked to its increased expression and intracellular transamidating activity. However, a full understanding of the molecular mechanisms involved still remains unclear despite numerous studies that have attempted to delineate this process. These mechanisms include the NFκB and TGFβ1 pathway amongst others. This study reveals for the first time that the development of fibrosis in CF is due to a TG2-driven epithelial to mesenchymal transition (EMT) via a mechanism involving the activation of the pro-fibrotic cytokine TGFβ1. Using a human ΔF508/W1282X CFTR CF mutant bronchial cell (IB3-1), its CFTR corrected “add-back” cell (C38) as well as a primary human bronchial epithelial cell (HBEC), elevated TG2 levels in the CFTR mutant IB3 cell were shown to activate latent TGFβ1 leading to increased levels found in the culture medium. This activation process was blocked by the presence of cell-permeable and impermeable TG2 inhibitors while inhibition of TGFβ1 receptors blocked TG2 expression. This demonstrates the direct link between TG2 and TGFβ1 in CF. The presence of active cell surface TG2 correlated with an increase in the expression of EMT markers, associated with the CF mutant cells, which could be blocked by the presence of TG2 inhibitors. This was mimicked using the “addback” C38 cell and the primary human bronchial epithelial cell, HBEC, where an increase in TG2 expression and activity in the presence of TGFβ1 concurred with a change in cell morphology and an elevation in EMT marker expression. Conversely, a knockdown of TG2 in the CF mutant IB3 cells illustrated that an inhibition of TG2 blocks the increase in EMT marker expression as well as causing an increase in TEER measurement. This together with an increase in the migration profile of the CF mutant IB3 cell against the “add-back” C38 cell suggests that TG2 drives a mesenchymal phenotype in CF. The involvement of TG2 activated TGFβ1 in CF was further demonstrated with an elevation/inhibition of p- SMAD 2 and 3 activation in the presence of TGFβ1/TG2 cell-permeable/impermeable inhibitors respectively. The use of a comparative airway cell model where bronchial epithelial cells were cultured at the air liquid interface (ALI) confirmed the observations in submerged culture depicting the robustness of the model and reiterated the importance of TG2 in CF. Using a CFTR corrector combined with TG2 inhibitors, this study showed that the correction and stabilisation of the ΔF508 CFTR mutation in the mutant cell forged an increase in matured CFTR copies trafficking to the apical surface by circumventing proteosomal degradation. Thus the results presented here suggests that TG2 expression is elevated in the CFTR mutant bronchial cell via a TGFβ1 driven positive feedback cycle whereby activation of latent TGFβ1 by TG2 leads in turn to an elevation in its own expression by TGFβ1. This vicious cycle then drives EMT in CF ultimately leading to lung remodelling and fibrosis. Importantly, TG2 inhibition blocks TGFβ1 activation leading to an inhibition of EMT and further blocks the emerging fibrosis, thus stabilizing and supporting the maturation, trafficking and conductance of CFTR channels at the apical surface.

Achievable performance gain of IEEE 802.11 multi-rate link adaptation algorithm with cross-layer design

Link quality-based rate adaptation has been widely used for IEEE 802.11 networks. However, network performance is affected by both link quality and random channel access. Selection of transmit modes for optimal link throughput can cause medium access control (MAC) throughput loss. In this paper, we investigate this issue and propose a generalised cross-layer rate adaptation algorithm. It considers jointly link quality and channel access to optimise network throughput. The objective is to examine the potential benefits by cross-layer design. An efficient analytic model is proposed to evaluate rate adaptation algorithms under dynamic channel and multi-user access environments. The proposed algorithm is compared to link throughput optimisation-based algorithm. It is found rate adaptation by optimising link layer throughput can result in large performance loss, which cannot be compensated by the means of optimising MAC access mechanism alone. Results show cross-layer design can achieve consistent and considerable performance gains of up to 20%. It deserves to be exploited in practical design for IEEE 802.11 networks.

Mechanism for cross-linking polychloroprene with ethylene thiourea and zinc oxide

An investigation into the mechanism by which ethylene thiourea (ETU) cross-links polychloroprene (CR) in combination with zinc oxide (ZnO) was undertaken. This was achieved through an examination of the mechanisms of crosslinking CR with ETU and ZnO separately and in unison. Spectroscopic and physical characterization techniques were employed to probe the cross-linking mechanisms of CRusing other standard rubber accelerators and model compounds with analogous structures and functionalities to ETU. These investigations have resulted in the proposal of a new mechanism by which ETU and ZnO can synergistically cross-link CR, in addition to providing new evidence to support concomitant mechanisms already published for cross-linking CR.

Annotated record of the detailed examination of Mn nodules recovered from the VA04 expedition (R/V Valdivia) in the Pacific Ocean

Twenty-four manganese nodules from the surface of the sea floor and fifteen buried nodules were studied. With three exceptions, the nodules were collected from the area covered by Valdivia Cruise VA 04 some 1200 nautical miles southeast of Hawaii. Age determinations were made using the ionium method. In order to get a true reproduction of the activity distribution in the nodules, they were cut in half and placed for one month on nuclear emulsion plates to determine the alpha-activity of the ionium and its daughter products. Special methods of counting the alpha-tracks resolution to depth intervals of 0.125 mm. For the first time it was possible to resolve zones of rapid growth (impulse growth) with growth rates, s > 50 mm/106 yr and interruptions in growth. With few exceptions the average rate of growth of all nodules was surprisingly uniform at 4-9 mm/10 yr. No growth could be recognized radioactively in the buried nodules. One exceptional nodule has had recent impulse growth and, in the material formed, the ionium is not yet in equilibrium with its daughter products. Individual layers in one nodule from the Indian Ocean could be dated and an average time interval of t = 2600±400 yr was necessary to form one layer. The alternation between iron and manganese-rich parts of the nodules was made visible by colour differences resulting from special treatment of cut surfaces with HCl vapour. The zones of slow growth of one nodule are relatively enriched in iron. Earlier attempts to find paleomagnetic reversals in manganese nodules have been continued. Despite considerable improvement in areal resolution, reversals were not detected in the nodules studied. Comparisons of the surface structure, microstructure in section and the radiometric dating show that there are erosion surfaces and growth surfaces on the outer surfaces of the manganese nodules. The formation of cracks in the nodules was studied in particular. The model of age-dependent nodule shrinkage and cracking surprisingly indicates that the nodules break after exceeding a certain age and/or size. Consequently, the breaking apart of manganese nodules is a continuous process not of catastrophic or discontinuous origin. The microstructure of the nodules exhibits differences in the mechanism of accretion and accretion rate of material, shortly referred to as accretion form. Thus non-directional growth inside the nodules as well as a directional growth may be observed. Those nodules with large accretion forms have grown faster than smaller ones. Consequently, parallel layers indicate slow growth. The upper surfaces of the nodules, protruding into the bottom water appear to be more prone to growth disturbances than the lower surfaces, immersed in the sediment. Features of some nodules show, that as they develop, they neither turned nor rolled. Yet unknown is the mechanism that keeps the nodules at the surface during continuous sedimentation. All in all, the nodules remain the objects of their own distinctive problems. The hope of using them as a kind of history book still seems to be very remote.

Design, development and control of a new generation high performance linear actuator for parallel robots and other applications

The main focus of this research is to design and develop a high performance linear actuator based on a four bar mechanism. The present work includes the detailed analysis (kinematics and dynamics), design, implementation and experimental validation of the newly designed actuator. High performance is characterized by the acceleration of the actuator end effector. The principle of the newly designed actuator is to network the four bar rhombus configuration (where some bars are extended to form an X shape) to attain high acceleration. Firstly, a detailed kinematic analysis of the actuator is presented and kinematic performance is evaluated through MATLAB simulations. A dynamic equation of the actuator is achieved by using the Lagrangian dynamic formulation. A SIMULINK control model of the actuator is developed using the dynamic equation. In addition, Bond Graph methodology is presented for the dynamic simulation. The Bond Graph model comprises individual component modeling of the actuator along with control. Required torque was simulated using the Bond Graph model. Results indicate that, high acceleration (around 20g) can be achieved with modest (3 N-m or less) torque input. A practical prototype of the actuator is designed using SOLIDWORKS and then produced to verify the proof of concept. The design goal was to achieve the peak acceleration of more than 10g at the middle point of the travel length, when the end effector travels the stroke length (around 1 m). The actuator is primarily designed to operate in standalone condition and later to use it in the 3RPR parallel robot. A DC motor is used to operate the actuator. A quadrature encoder is attached with the DC motor to control the end effector. The associated control scheme of the actuator is analyzed and integrated with the physical prototype. From standalone experimentation of the actuator, around 17g acceleration was achieved by the end effector (stroke length was 0.2m to 0.78m). Results indicate that the developed dynamic model results are in good agreement. Finally, a Design of Experiment (DOE) based statistical approach is also introduced to identify the parametric combination that yields the greatest performance. Data are collected by using the Bond Graph model. This approach is helpful in designing the actuator without much complexity.

The Catalytic Mechanism of the Marine-Derived Macrocyclase, PATGmac

Acknowledgements This work received financial support from the European Union (FEDER funds through COMPETE) and National Funds (FCT, Fundação para a Ciência e Tecnologia) through Projects EXCL/QEQ-COM/ 0394/2012, EXCL-II/QEQ-COM/0394/2012, and Pest-C/EQB/LA0006/2013. NFB would like to thank the Fundação para a Ciência e a Tecnologia (FCT) for her IF starting grant (IF/01355/2014).

Two parallel, pragmatic, UK multicentre, randomised controlled trials comparing surgical options for upper compartment (vault or uterine) pelvic organ prolapse (the VUE Study) : study protocol for a randomised controlled trial

The VUE study is funded by the National Institute for Health Research Health Technology Assessment programme (project number 11/129/183).

Conceptual designs of multi-degree of freedom compliant parallel manipulators composed of wire-beam based compliant mechanisms

This paper proposes conceptual designs of multi-degree(s) of freedom (DOF) compliant parallel manipulators (CPMs) including 3-DOF translational CPMs and 6-DOF CPMs using a building block based pseudo-rigid-body-model (PRBM) approach. The proposed multi-DOF CPMs are composed of wire-beam based compliant mechanisms (WBBCMs) as distributed-compliance compliant building blocks (CBBs). Firstly, a comprehensive literature review for the design approaches of compliant mechanisms is conducted, and a building block based PRBM is then presented, which replaces the traditional kinematic sub-chain with an appropriate multi-DOF CBB. In order to obtain the decoupled 3-DOF translational CPMs (XYZ CPMs), two classes of kinematically decoupled 3-PPPR (P: prismatic joint, R: revolute joint) translational parallel mechanisms (TPMs) and 3-PPPRR TPMs are identified based on the type synthesis of rigid-body parallel mechanisms, and WBBCMs as the associated CBBs are further designed. Via replacing the traditional actuated P joint and the traditional passive PPR/PPRR sub-chain in each leg of the 3-DOF TPM with the counterpart CBBs (i.e. WBBCMs), a number of decoupled XYZ CPMs are obtained by appropriate arrangements. In order to obtain the decoupled 6-DOF CPMs, an orthogonally-arranged decoupled 6-PSS (S: spherical joint) parallel mechanism is first identified, and then two example 6-DOF CPMs are proposed by the building block based PRBM method. It is shown that, among these designs, two types of monolithic XYZ CPM designs with extended life have been presented.

A completely kinematostatically decoupled XY compliant parallel manipulator through new topology structure

This paper deals with a completely kinematostaticaly decoupled XY compliant parallel manipulator (CPM) composed of exactly-constrained compliant modules. A new 4-PP XY translational parallel mechanism (TPM) with a new topology structure is firstly proposed where each two P (P: prismatic) joints on the base in two non-adjacent legs are rigidly connected. A novel 4-PP XY CPM is then obtained by replacing each traditional P join on the base in the 4-PP XY TPM with a compound basic parallelogram module (CBPM) and replacing each traditional P joint on the motion stage with a basic parallelogram module (BPM). Approximate analytical model is derived with comparison to the FEA (finite element analysis) model and experiment for a case study. The proposed novel XY CPM has a compact configuration with good dynamics, and is able to well constrain the parasitic rotation and the cross-axis coupling of the motion stage. The cross-axis motion of the input stage can be completely eliminated, and the lost motion between the input stage and the motion stage is significantly reduced.

Design and analysis of a compliant parallel pan-tilt platform

In combination of the advantages of both parallel mechanisms and compliant mechanisms, a compliant parallel mechanism with two rotational DOFs (degrees of freedom) is designed to meet the requirement of a lightweight and compact pan-tilt platform. Firstly, two commonly-used design methods i.e. direct substitution and FACT (Freedom and Constraint Topology) are applied to design the configuration of the pan-tilt system, and similarities and differences of the two design alternatives are compared. Then inverse kinematic analysis of the candidate mechanism is implemented by using the pseudo-rigid-body model (PRBM), and the Jacobian related to its differential kinematics is further derived to help designer realize dynamic analysis of the 8R compliant mechanism. In addition, the mechanism’s maximum stress existing within its workspace is tested by finite element analysis. Finally, a method to determine joint damping of the flexure hinge is presented, which aims at exploring the effect of joint damping on actuator selection and real-time control. To the authors’ knowledge, almost no existing literature concerns with this issue.

Link between increased gut hormones signaling satiety and reduced food reward following gastric bypass surgery for obesity

CONTEXT: Roux-en-Y gastric bypass (RYGB) surgery is an effective long-term intervention for weight loss maintenance, reducing appetite, and also food reward, via unclear mechanisms. OBJECTIVE: To investigate the role of elevated satiety gut hormones after RYGB, we examined food hedonic-reward responses after their acute post-prandial suppression. DESIGN: These were randomized, placebo-controlled, double-blind, crossover experimental medicine studies. PATIENTS: Two groups, more than 5 months after RYGB for obesity (n = 7-11), compared with nonobese controls (n = 10), or patients after gastric banding (BAND) surgery (n = 9) participated in the studies. INTERVENTION: Studies were performed after acute administration of the somatostatin analog octreotide or saline. In one study, patients after RYGB, and nonobese controls, performed a behavioral progressive ratio task for chocolate sweets. In another study, patients after RYGB, and controls after BAND surgery, performed a functional magnetic resonance imaging food picture evaluation task. MAIN OUTCOME MEASURES: Octreotide increased both appetitive food reward (breakpoint) in the progressive ratio task (n = 9), and food appeal (n = 9) and reward system blood oxygen level-dependent signal (n = 7) in the functional magnetic resonance imaging task, in the RYGB group, but not in the control groups. RESULTS: Octreotide suppressed postprandial plasma peptide YY, glucagon-like peptide-1, and fibroblast growth factor-19 after RYGB. The reduction in plasma peptide YY with octreotide positively correlated with the increase in brain reward system blood oxygen level-dependent signal in RYGB/BAND subjects, with a similar trend for glucagon-like peptide-1. CONCLUSIONS: Enhanced satiety gut hormone responses after RYGB may be a causative mechanism by which anatomical alterations of the gut in obesity surgery modify behavioral and brain reward responses to food.