Active control of buckling of flexible beams

The feasibility of using the rapidly growing technology of the shape memory alloys actuators in actively controlling the buckling of large flexible structures is investigated. The need for such buckling control systems is becoming inevitable as the design trends of large space structures have resulted in the use of structural members that are long, slender, and very flexible. In addition, as these truss members are subjected mainly to longitudinal loading they become susceptible to structural instabilities due to buckling. Proper control of such instabilities is essential to the effective performance of the structures as stable platforms for communication and observation. Mathematical models are presented that simulate the dynamic characteristics of the shape memory actuator, the compressive structural members, and the associated active control system. A closed-loop computer-controlled system is designed, based on the developed mathematical models, and implemented to control the buckling of simple beams. The performance of the computer-controlled system is evaluated experimentally and compared with the theoretical predictions to validate the developed models. The obtained results emphasize the importance of buckling control and suggest the potential of the shape memory actuators as attractive means for controlling structural deformation in a simple and reliable way

Structural arrangement of the transmission interface in the antigen ABC transport complex TAP

The transporter associated with antigen processing (TAP) represents a focal point in the immune recognition of virally or malignantly transformed cells by translocating proteasomal degradation products into the endoplasmic reticulum–lumen for loading of MHC class I molecules. Based on a number of experimental data and the homology to the bacterial ABC exporter Sav1866, we constructed a 3D structural model of the core TAP complex and used it to examine the interface between the transmembrane and nucleotide-binding domains (NBD) by cysteine-scanning and cross-linking approaches. Herein, we demonstrate the functional importance of the newly identified X-loop in the NBD in coupling substrate binding to downstream events in the transport cycle. We further verified domain swapping in a heterodimeric ABC half-transporter complex by cysteine cross-linking. Strikingly, either substrate binding or translocation can be blocked by cross-linking the X-loop to coupling helix 2 or 1, respectively. These results resolve the structural arrangement of the transmission interface and point to different functions of the cytosolic loops and coupling helices in substrate binding, signaling, and transport

HLA-DM Mediates Epitope Selection by a “Compare-Exchange” Mechanism when a Potential Peptide Pool Is Available

BACKGROUND: HLA-DM (DM) mediates exchange of peptides bound to MHC class II (MHCII) during the epitope selection process. Although DM has been shown to have two activities, peptide release and MHC class II refolding, a clear characterization of the mechanism by which DM facilitates peptide exchange has remained elusive. METHODOLOGY/PRINCIPAL FINDINGS: We have previously demonstrated that peptide binding to and dissociation from MHCII in the absence of DM are cooperative processes, likely related to conformational changes in the peptide-MHCII complex. Here we show that DM promotes peptide release by a non-cooperative process, whereas it enhances cooperative folding of the exchange peptide. Through electron paramagnetic resonance (EPR) and fluorescence polarization (FP) we show that DM releases prebound peptide very poorly in the absence of a candidate peptide for the exchange process. The affinity and concentration of the candidate peptide are also important for the release of the prebound peptide. Increased fluorescence energy transfer between the prebound and exchange peptides in the presence of DM is evidence for a tetramolecular complex which resolves in favor of the peptide that has superior folding properties. CONCLUSION/SIGNIFICANCE: This study shows that both the peptide releasing activity on loaded MHCII and the facilitating of MHCII binding by a candidate exchange peptide are integral to DM mediated epitope selection. The exchange process is initiated only in the presence of candidate peptides, avoiding possible release of a prebound peptide and loss of a potential epitope. In a tetramolecular transitional complex, the candidate peptides are checked for their ability to replace the pre-bound peptide with a geometry that allows the rebinding of the original peptide. Thus, DM promotes a "compare-exchange" sorting algorithm on an available peptide pool. Such a "third party"-mediated mechanism may be generally applicable for diverse ligand recognition in other biological systems

Bone Morphogenetic Protein (BMP)-7 expression is decreased in human hypertensive nephrosclerosis

Background: Bone Morphogenetic Protein (BMP)-7 is protective in different animal models of acute and chronic kidney disease. Its role in human kidneys, and in particular hypertensive nephrosclerosis, has thus far not been described. Methods: BMP-7 mRNA was quantified using real-time PCR and localised by immunostaining in tissue samples from normal and nephrosclerotic human kidneys. The impact of angiotensin (AT)-II and the AT-II receptor antagonist telmisartan on BMP-7 mRNA levels and phosphorylated Smad 1/5/8 (pSmad 1/5/8) expression was quantified in proximal tubular cells (HK-2). Functional characteristics of BMP-7 were evaluated by testing its influence on TGF-b induced epithelial-to-mesenchymal transition (EMT), expression of TGF-b receptor type I (TGF-bRI) and phosphorylated Smad 2 (pSmad 2) as well as on TNF-a induced apoptosis of proximal tubular cells. Results: BMP-7 was predominantly found in the epithelia of the distal tubule and the collecting duct and was less abundant in proximal tubular cells. In sclerotic kidneys, BMP-7 was significantly decreased as demonstrated by real-time PCR and immunostaining. AT-II stimulation in HK-2 cells led to a significant decrease of BMP-7 and pSmad 1/5/8, which was partially ameliorated upon co-incubation with telmisartan. Only high concentrations of BMP-7 (100 ng/ml) were able to reverse TNF-a-induced apoptosis and TGF-b-induced EMT in human proximal tubule cells possibly due to a decreased expression of TGF-bRI. In addition, BMP-7 was able to reverse TGF-b-induced phosphorylation of Smad 2. Conclusions: The findings suggest a protective role for BMP-7 by counteracting the TGF-b and TNF-a-induced negative effects. The reduced expression of BMP-7 in patients with hypertensive nephrosclerosis may imply loss of protection and regenerative potential necessary to counter the disease

When workplace unionism in global value chains does not function well : exploring the impediments

Improving working conditions at the bottom of global value chains has become a central issue in our global economy. In this battle, trade unionism has been presented as a way for workers to make their voices heard. Therefore, it is strongly promoted by most social standards. However, establishing a well-functioning trade union is not as obvious as it may seem. Using a comparative case study approach, we examine impediments to farm-level unionism in the cut flower industry in Ethiopia. For this purpose, we propose an integrated framework combining two lenses, namely a vertical one (governance and structure of global value chains) and a horizontal one (socio-economic context). We identify 10 impediments that point to three major dimensions contributing to unionisation. These three dimensions include awareness of and interest from workers, legitimacy of trade unions, and capacity of trade unions to act. Furthermore, our results suggest that private social standards may, in certain cases, be counterproductive for the efficient functioning of trade unions. Although we argue that there is no ‘quick fix’ solution to weak workplace unionism at the bottom of global value chains, we stress the importance of considering the dynamics of, and interactions between, the impediments when designing potential support measures that mitigate negative impacts

Blocking TGF-β signaling pathway preserves mitochondrial proteostasis and reduces early activation of PDGFRβ+ pericytes in aristolochic acid induced acute kidney injury in wistar male rats

The platelet-derived growth factor receptor β (PDGFRβ)+ perivascular cell activation becomes increasingly recognized as a main source of scar-associated kidney myofibroblasts and recently emerged as a new cellular therapeutic target.In this regard, we first confirmed the presence of PDGFRβ+ perivascular cells in a human case of end-stage aristolochic acid nephropathy (AAN) and thereafter we focused on the early fibrosis events of transforming growth factor β (TGFβ) inhibition in a rat model of AAN.Neutralizing anti-TGFβ antibody (1D11) and its control isotype (13C4) were administered (5 mg/kg, i.p.) at Days -1, 0, 2 and 4; AA (15 mg/kg, sc) was injected daily.At Day 5, 1D11 significantly suppressed p-Smad2/3 signaling pathway improving renal function impairment, reduced the score of acute tubular necrosis, peritubular capillaritis, interstitial inflammation and neoangiogenesis. 1D11 markedly decreased interstitial edema, disruption of tubular basement membrane loss of brush border, cytoplasmic edema and organelle ultrastructure alterations (mitochondrial disruption and endoplasmic reticulum edema) in proximal tubular epithelial cells. Moreover, 1D11 significantly inhibited p-PERK activation and attenuated dysregulation of unfolded protein response (UPR) pathways, endoplasmic reticulum and mitochondrial proteostasis in vivo and in vitro.The early inhibition of p-Smad2/3 signaling pathway improved acute renal function impairment, partially prevented epithelial-endothelial axis activation by maintaining PTEC proteostasis and reduced early PDGFRβ+ pericytes-derived myofibroblasts accumulation

What is damaging the kidney in lupus nephritis?

Despite marked improvements in the survival of patients with severe lupus nephritis over the past 50 years, the rate of complete clinical remission after immune suppression therapy i

The challenge of implementing voluntary sustainability standards: a dynamic framework on the tension between adherence and adaptation

Voluntary sustainability standards (VSS) aim to encourage ethical behaviors of organizations, yet studies show that many VSS adopters do not live up to these promises. Existing literature typically attributes the reason for this ineffectiveness to either policy-practice decoupling, owing to a lack of adhering to VSS requirements, or means-ends decoupling, owing to a lack of adapting to the local context. However, little is known about how the contradictory needs of adherence and adaptation evolve throughout VSS implementation. Building on the knowledge transfer literature, we develop a dynamic conceptual framework that distinguishes two phases of VSS implementation. Specifically, we theorize how tensions emerge in the transition between phases since the first phase primarily calls for adherence, whereas the second calls for adaptation. Applying this framework, we develop propositions to illustrate how these tensions relate to different VSS characteristics: stringency, enforcement, and scope. The article concludes with implications and future research directions for VSS scholarship

Atp-lipids - protein anchor and energy source in two dimensions

The ubiquitous function of ATP as energy equivalent in nature has resulted in a common folding pattern of ATP-binding proteins. Their binding pocket tolerates modifications of the adenine ring to some extend, whereas those of the triphosphate group strongly affect the binding affinity. In consequence, immobilized C8- and N-6- modified ATP analogues are frequently used for affinity purification of ATPases or kinases. To combine this unique recognition principle with the fascinating properties of self-assembly, we have synthesized a novel class of hydrolyzable and nonhydrolyzable ATP-lipids where the nucleotides are covalently attached via C8- or N-6-position of the adenine ring to a synthetic lipid. These ATP-lipids were characterized by various enzyme assays in micellar solution, resulting in ATPase and competition activities that are comparable to their free counterparts. The specific docking of actin as a model of an ATP-binding protein to ATP-lipid monolayers was followed by film balance technique and epifluorescence microscopy. Based on this specific interaction, actin-supported membranes were generated to study shape transitions of vesicular systems. Due to the coupling of actin to ATP-lipid bilayers drastic changes in the viscoelastic properties and shape transitions were observed by phase contrast microscopy. These results underline the properties of these novel ATP-lipids as protein anchor or energy source in two dimensions. They can be applied either to form phantom cells, actin-supported membranes or to orient and crystallize ATP-binding proteins at lipid interfaces. [References: 81