Protein disulfide isomerase: the structure of oxidative folding

Cellular functions hinge on the ability of proteins to adopt their correct folds, and misfolded proteins can lead to disease. Here, we focus on the proteins that catalyze disulfide bond formation, a step in the oxidative folding pathway that takes place in specialized cellular compartments. In the endoplasmic reticulum of eukaryotes, disulfide formation is catalyzed by protein disulfide isomerase (PDI); by contrast, prokaryotes produce a family of disulfide bond (Dsb) proteins, which together achieve an equivalent outcome in the bacterial periplasm. The recent crystal structure of yeast PDI has increased our understanding of the function and mechanism of PDI. Comparison of the structure of yeast PDI with those of bacterial DsbC and DsbG reveals some similarities but also striking differences that suggest directions for future research aimed at unraveling the catalytic mechanism of disulfide bond formation in the cell.

Is economic philosophy a subject worth teaching?

Economic philosophy is anything but a part of the mainstream diet in the course of an economics education. Yet there are those – including occasional Nobel prizewinners – who argue that an understanding of economic philosophy is absolutely fundamental to an understanding of economics, of why economists disagree and of why “economic rationalists” are often derided by those from other professional backgrounds. The argument put in this paper is that many social science debates hinge more on the values or social philosophy implicitly involved than on technical matters of economic 'science', and that a nuanced understanding of economics requires that each school of thought be traced back to its foundations in terms of its implicit economic philosophy a prioris.

Interaction of calcitonin-gene-related peptide with its receptors

The receptor for calcitonin-gene-related peptide (CGRP) is a heterodimer formed by calcitonin-receptor-like receptor (CRLR), a type II (family B) G-protein-coupled receptor, and receptor-activity-modifying protein 1 (RAMP1), a single-membrane-pass protein. It is likely that the first seven or so amino acids of CGRP (which form a disulphide-bonded loop) interact with the transmembrane domain of CRLR to cause receptor activation. The rest of the CGRP molecule falls into three domains. Residues 28-37 and 8-18 are normally required for high-affinity binding, while residues 19-27 form a hinge region. The 28-37 region is almost certainly in direct contact with the receptor; 8-18 may make additional receptor contacts or may stabilize an appropriate conformation of 28-37. It is likely that these regions of CGRP interact both with CRLR and with the extracellular domain of RAMP1.

Effect of polymorph derived oxidants on IgG in relation to rheumatoid factor binding

Immunoglobulin G from rheumatoid patients is denatured around the hinge region. This has been proposed as an explanation for the presence of circulating autoantibodies to IgG in these patients. It has previously been suggested that oxygen radicals (OR) derived from activated polymorphs may play a role in denaturation in vivo. Using sera from rheumatoid patients and age-matched controls in a modified ELISA technique, we have investigated the potential for polyclonal rheumatoid factors (RF) to bind to OR denatured IgG. Three model systems were used to generate OR in vitro: (a) purified PMN s activated by the cell surface stimulant PMA, (b) radiolysis of IgG in solution to generate specifically the superoxide radical and, in a separate system, the hydroxyl radical, (OH.), (c) purified myeloperoxide in the presence of H2O2 and halide ions. Results: 1. The binding of both IgA and IgM RF s to PMN denatured IgG increased dose dependently for seropositive sera only. 2. The OH. radical but not the superoxide radical significantly increased the binding of IgA and M RF, again only for seropositive sera. 3. The myeloperoxidase enzyme system did not increase RF binding. 4. IgG incubated with elastase was not found to be a better antigen than native IgG. These results indicate that IgG is denatured by OR released from activated PMN, thereby producing an antigen for polyclonal RF s.

Mechanism of action of the tetraflex accommodative intraocular lens

PURPOSE:To investigate the mechanism of action of the Tetraflex (Lenstec Kellen KH-3500) accommodative intraocular lens (IOL). METHODS:Thirteen eyes of eight patients implanted with the Tetraflex accommodating IOL for at least 2 years underwent assessment of their objective amplitude-of-accommodation by autorefraction, anterior chamber depth and pupil size with optical coherence tomography, and IOL flexure with aberrometry, each viewing a target at 0.0 to 4.00 diopters of accommodative demand. RESULTS:Pupil size decreased by 0.62+/-0.41 mm on increasing accommodative demand, but the Tetraflex IOL was relatively fixed in position within the eye. The ocular aberrations of the eye changed with increased accommodative demand, but not in a consistent manner among individuals. Those aberrations that appeared to be most affected were defocus, vertical primary and secondary astigmatism, vertical coma, horizontal and vertical primary and secondary trefoil, and spherical aberration. CONCLUSIONS:Some of the reported near vision benefits of the Tetraflex accommodating IOL appear to be due to changes in the optical aberrations because of the flexure of the IOL on accommodative effort rather than forward movement within the capsular bag.

Analysis of flexural isostasy of the northern Andes

The mode in which a lithosphere plate supports overlying topography is greatly driven by the strength of the plate. By analyzing the geophysical signature of lithosphere flexure, in the space and spectral domains, the strength of the plates that support the north Andean mountains and adjacent basins, and the topography of Kenya was investigated. In addition, the effect of windowing on elastic thickness estimates obtained via the coherence method was evaluated. ^ The coherence between the topography and Bouguer gravity spectra of northern South America suggests that the average elastic thickness of the lithosphere is 30 km. Although lateral variations were not resolved by the coherence implementation, these became apparent by modeling the foreland stratigraphy of the Llanos, Barinas and Maracaibo sub-Andean basins. Flexural models reveal a zone of lithosphere weakness beneath the eastern flank of the Eastern Cordillera and western flank of the Venezuelan Andes. The gravity anomaly calculated from these models is consistent with the observed Bouguer gravity anomaly. This zone of weakness appears to separate the strong, old Guyana shield lithosphere from the weaker and probably younger Andean lithosphere. The zone of weakness may correspond to a Paleozoic feature at the western margin of cratonic South America, or a Mesozoic rift arm that weakened the proto-Andean lithosphere. ^ Using synthetic data as well as the northern South America topography and gravity, this study demonstrates that lithosphere strength calculated from the coherence of mirrored data may overestimate the true lithosphere strength. As a result, many lithosphere plates may be weaker than currently thought. In light of this observation, gravity and topography data from Kenya were reevaluated using multitaper spectral techniques. The elastic thickness of this plate, currently undergoing rifting, was estimated at 7 to 8 km, a factor of 2 less than previously estimated. These estimates suggest that despite intense fracturing and sustained tensile stresses, continental lithosphere plates undergoing rifting are able to retain some strength. ^

Seismic performance of hybrid fiber reinforced polymer-concrete pier frame systems

As an alternative to transverse spiral or hoop steel reinforcement, fiber reinforced polymers (FRPs) were introduced to the construction industry in the 1980’s. The concept of concrete-filled FRP tube (CFFT) has raised great interest amongst researchers in the last decade. FRP tube can act as a pour form, protective jacket, and shear and flexural reinforcement for concrete. However, seismic performance of CFFT bridge substructure has not yet been fully investigated. Experimental work in this study included four two-column bent tests, several component tests and coupon tests. Four 1/6-scale bridge pier frames, consisting of a control reinforced concrete frame (RCF), glass FRP-concrete frame (GFF), carbon FRP-concrete frame (CFF), and hybrid glass/carbon FRP-concrete frame (HFF) were tested under reverse cyclic lateral loading with constant axial loads. Specimen GFF did not show any sign of cracking at a drift ratio as high as 15% with considerable loading capacity, whereas Specimen CFF showed that lowest ductility with similar load capacity as in Specimen GFF. FRP-concrete columns and pier cap beams were then cut from the pier frame specimens, and were tested again in three point flexure under monotonic loading with no axial load. The tests indicated that bonding between FRP and concrete and yielding of steel both affect the flexural strength and ductility of the components. The coupon tests were carried out to establish the tensile strength and elastic modulus of each FRP tube and the FRP mold for the pier cap beam in the two principle directions of loading. A nonlinear analytical model was developed to predict the load-deflection responses of the pier frames. The model was validated against test results. Subsequently, a parametric study was conducted with variables such as frame height to span ratio, steel reinforcement ratio, FRP tube thickness, axial force, and compressive strength of concrete. A typical bridge was also simulated under three different ground acceleration records and damping ratios. Based on the analytical damage index, the RCF bridge was most severely damaged, whereas the GFF bridge only suffered minor repairable damages. Damping ratio was shown to have a pronounced effect on FRP-concrete bridges, just the same as in conventional bridges. This research was part of a multi-university project, which is founded by the National Science Foundation (NSF) - Network for Earthquake Engineering Simulation Research (NEESR) program.

Seismic performance of hybrid fiber reinforced polymer-concrete pier columns

As part of a multi-university research program funded by NSF, a comprehensive experimental and analytical study of seismic behavior of hybrid fiber reinforced polymer (FRP)-concrete column is presented in this dissertation. Experimental investigation includes cyclic tests of six large-scale concrete-filled FRP tube (CFFT) and RC columns followed by monotonic flexural tests, a nondestructive evaluation of damage using ultrasonic pulse velocity in between the two test sets and tension tests of sixty-five FRP coupons. Two analytical models using ANSYS and OpenSees were developed and favorably verified against both cyclic and monotonic flexural tests. The results of the two methods were compared. A parametric study was also carried out to investigate the effect of three main parameters on primary seismic response measures. The responses of typical CFFT columns to three representative earthquake records were also investigated. The study shows that only specimens with carbon FRP cracked, whereas specimens with glass or hybrid FRP did not show any visible cracks throughout cyclic tests. Further monotonic flexural tests showed that carbon specimens both experienced flexural cracks in tension and crumpling in compression. Glass or hybrid specimens, on the other hand, all showed local buckling of FRP tubes. Compared with conventional RC columns, CFFT column possesses higher flexural strength and energy dissipation with an extended plastic hinge region. Among all CFFT columns, the hybrid lay-up demonstrated the highest flexural strength and initial stiffness, mainly because of its high reinforcement index and FRP/concrete stiffness ratio, respectively. Moreover, at the same drift ratio, the hybrid lay-up was also considered as the best in term of energy dissipation. Specimens with glassfiber tubes, on the other hand, exhibited the highest ductility due to better flexibility of glass FRP composites. Furthermore, ductility of CFFTs showed a strong correlation with the rupture strain of FRP. Parametric study further showed that different FRP architecture and rebar types may lead to different failure modes for CFFT columns. Transient analysis of strong ground motions showed that the column with off-axis nonlinear filament-wound glass FRP tube exhibited a superior seismic performance to all other CFFTs. Moreover, higher FRP reinforcement ratios may lead to a brittle system failure, while a well-engineered FRP reinforcement configuration may significantly enhance the seismic performance of CFFT columns.

Predator–prey naïveté, antipredator behavior, and the ecology of predator invasions

We present a framework for explaining variation in predator invasion success and predator impacts on native prey that integrates information about predator–prey naïveté, predator and prey behavioral responses to each other, consumptive and non-consumptive effects of predators on prey, and interacting effects of multiple species interactions. We begin with the ‘naïve prey’ hypothesis that posits that naïve, native prey that lack evolutionary history with non-native predators suffer heavy predation because they exhibit ineffective antipredator responses to novel predators. Not all naïve prey, however, show ineffective antipredator responses to novel predators. To explain variation in prey response to novel predators, we focus on the interaction between prey use of general versus specific cues and responses, and the functional similarity of non-native and native predators. Effective antipredator responses reduce predation rates (reduce consumptive effects of predators, CEs), but often also carry costs that result in non-consumptive effects (NCEs) of predators. We contrast expected CEs versus NCEs for non-native versus native predators, and discuss how differences in the relative magnitudes of CEs and NCEs might influence invasion dynamics. Going beyond the effects of naïve prey, we discuss how the ‘naïve prey’, ‘enemy release’ and ‘evolution of increased competitive ability’ (EICA) hypotheses are inter-related, and how the importance of all three might be mediated by prey and predator naïveté. These ideas hinge on the notion that non-native predators enjoy a ‘novelty advantage’ associated with the naïveté of native prey and top predators. However, non-native predators could instead suffer from a novelty disadvantage because they are also naïve to their new prey and potential predators. We hypothesize that patterns of community similarity and evolution might explain the variation in novelty advantage that can underlie variation in invasion outcomes. Finally, we discuss management implications of our framework, including suggestions for managing invasive predators, predator reintroductions and biological control.

Are marginalized women being left behind? A population-based study of institutional deliveries in Karnataka, India

Background While India has made significant progress in reducing maternal mortality, attaining further declines will require increased skilled birth attendance and institutional delivery among marginalized and difficult to reach populations. Methods A population-based survey was carried out among 16 randomly selected rural villages in rural Mysore District in Karnataka, India between August and September 2008. All households in selected villages were enumerated and women with children 6 years of age or younger underwent an interviewer-administered questionnaire on antenatal care and institutional delivery. Results Institutional deliveries in rural areas of Mysore District increased from 51% to 70% between 2002 and 2008. While increasing numbers of women were accessing antenatal care and delivering in hospitals, large disparities were found in uptake of these services among different castes. Mothers belonging to general castes were almost twice as likely to have an institutional birth as compared to scheduled castes and tribes. Mothers belonging to other backward caste or general castes had 1.8 times higher odds (95% CI: 1.21, 2.89) of having an institutional delivery as compared to scheduled castes and tribes. In multivariable analysis, which adjusted for inter- and intra-village variance, Below Poverty Line status, caste, and receiving antenatal care were all associated with institutional delivery. Conclusion The results of the study suggest that while the Indian Government has made significant progress in increasing antenatal care and institutional deliveries among rural populations, further success in lowering maternal mortality will likely hinge on the success of NRHM programs focused on serving marginalized groups. Health interventions which target SC/ST may also have to address both perceived and actual stigma and discrimination, in addition to providing needed services. Strategies for overcoming these barriers may include sensitization of healthcare workers, targeted health education and outreach, and culturally appropriate community-level interventions. Addressing the needs of these communities will be critical to achieving Millennium Development Goal Five by 2015.

Development of thresholds for surface preparation in repair systems with wet lay -up fiber reinforced polymers

Bonded repair of concrete structures with fiber reinforced polymer (FRP) systems is increasingly being accepted as a cost-efficient and structurally viable method of rapid rehabilitation of concrete structures. However, the relationships between long-term performance attributes, service-life, and details of the installation process are not easy to quantify. Accordingly, there is currently a lack of generally accepted construction specifications, making it difficult for the field engineer to certify the adequacy of the construction process. ^ The objective of the present study, as part of the National Cooperative Highway Research Program (NCHRP) Project 10-59B, was to investigate the effect of surface preparation on the behavior of wet lay-up FRP repair systems and consequently develop rational thresholds that provide sufficient performance. ^ The research program was comprised of both experimental and analytical work for wet lay-up FRP applications. The experimental work included flexure testing of sixty-seven (67) reinforced concrete beams and bond testing of ten (10) reinforced concrete blocks. Four different parameters were studied: surface roughness, surface flatness, surface voids and bug holes, and surface cracks/cuts. The findings were analyzed from various aspects and compared with the data available in the literature. As part of the analytical work, finite element models of the flexural specimens with surface flaws were developed using ANSYS. The purpose of this part was to extend the parametric study on the effects of concrete surface flaws and verify the experimental results based on nonlinear finite element analysis. ^ Test results showed that surface roughness does not appear to have a significant influence on the overall performance of the wet lay-up FRP systems with or without adequate anchorage, and whether failure was by debonding or rupture of FRP. Both experimental and analytical results for surface flatness proved that peaks on concrete surface, in the range studied, do not have a significant effect on the performance of wet lay-up FRP systems. However, valleys of particular size could reduce the strength of wet lay-up FRP systems. Test results regarding surface voids and surface cracks/cuts revealed that previously suggested thresholds for these flaws appear to be conservative, as also confirmed by analytical study. ^

Movement Effects on the Flow Physics and Nutrient Delivery in Engineered Valvular Tissues

Mechanical conditioning has been shown to promote tissue formation in a wide variety of tissue engineering efforts. However the underlying mechanisms by which external mechanical stimuli regulate cells and tissues are not known. This is particularly relevant in the area of heart valve tissue engineering (HVTE) owing to the intense hemodynamic environments that surround native valves. Some studies suggest that oscillatory shear stress (OSS) caused by steady flow and scaffold flexure play a critical role in engineered tissue formation derived from bone marrow derived stem cells (BMSCs). In addition, scaffold flexure may enhance nutrient (e.g. oxygen, glucose) transport. In this study, we computationally quantified the i) magnitude of fluid-induced shear stresses; ii) the extent of temporal fluid oscillations in the flow field using the oscillatory shear index (OSI) parameter, and iii) glucose and oxygen mass transport profiles. Noting that sample cyclic flexure induces a high degree of oscillatory shear stress (OSS), we incorporated moving boundary computational fluid dynamic simulations of samples housed within a bioreactor to consider the effects of: 1) no flow, no flexure (control group), 2) steady flow-alone, 3) cyclic flexure-alone and 4) combined steady flow and cyclic flexure environments. We also coupled a diffusion and convention mass transport equation to the simulated system. We found that the coexistence of both OSS and appreciable shear stress magnitudes, described by the newly introduced parameter OSI-t , explained the high levels of engineered collagen previously observed from combining cyclic flexure and steady flow states. On the other hand, each of these metrics on its own showed no association. This finding suggests that cyclic flexure and steady flow synergistically promote engineered heart valve tissue production via OSS, so long as the oscillations are accompanied by a critical magnitude of shear stress. In addition, our simulations showed that mass transport of glucose and oxygen is enhanced by sample movement at low sample porosities, but did not play a role in highly porous scaffolds. Preliminary in-house in vitro experiments showed that cell proliferation and phenotype is enhanced in OSI-t environments.

Regulation of Bone Marrow Stem Cells through Oscillatory Shear Stresses - A Heart Valve Tissue Engineering Perspective

Heart valve disease occurs in adults as well as in pediatric population due to age-related changes, rheumatic fever, infection or congenital condition. Current treatment options are limited to mechanical heart valve (MHV) or bio-prosthetic heart valve (BHV) replacements. Lifelong anti-coagulant medication in case of MHV and calcification, durability in case of BHV are major setbacks for both treatments. Lack of somatic growth of these implants require multiple surgical interventions in case of pediatric patients. Advent of stem cell research and regenerative therapy propose an alternative and potential tissue engineered heart valves (TEHV) treatment approach to treat this life threatening condition. TEHV has the potential to promote tissue growth by replacing and regenerating a functional native valve. Hemodynamics play a crucial role in heart valve tissue formation and sustained performance. The focus of this study was to understand the role of physiological shear stress and flexure effects on de novo HV tissue formation as well as resulting gene and protein expression. A bioreactor system was used to generate physiological shear stress and cyclic flexure. Human bone marrow mesenchymal stem cell derived tissue constructs were exposed to native valve-like physiological condition. Responses of these tissue constructs to the valve-relevant stress states along with gene and protein expression were investigated after 22 days of tissue culture. We conclude that the combination of steady flow and cyclic flexure helps support engineered tissue formation by the co-existence of both OSS and appreciable shear stress magnitudes, and potentially augment valvular gene and protein expression when both parameters are in the physiological range.

Seismic Performance of Hybrid Fiber Reinforced Polymer-Concrete Pier Columns

As part of a multi-university research program funded by NSF, a comprehensive experimental and analytical study of seismic behavior of hybrid fiber reinforced polymer (FRP)-concrete column is presented in this dissertation. Experimental investigation includes cyclic tests of six large-scale concrete-filled FRP tube (CFFT) and RC columns followed by monotonic flexural tests, a nondestructive evaluation of damage using ultrasonic pulse velocity in between the two test sets and tension tests of sixty-five FRP coupons. Two analytical models using ANSYS and OpenSees were developed and favorably verified against both cyclic and monotonic flexural tests. The results of the two methods were compared. A parametric study was also carried out to investigate the effect of three main parameters on primary seismic response measures. The responses of typical CFFT columns to three representative earthquake records were also investigated. The study shows that only specimens with carbon FRP cracked, whereas specimens with glass or hybrid FRP did not show any visible cracks throughout cyclic tests. Further monotonic flexural tests showed that carbon specimens both experienced flexural cracks in tension and crumpling in compression. Glass or hybrid specimens, on the other hand, all showed local buckling of FRP tubes. Compared with conventional RC columns, CFFT column possesses higher flexural strength and energy dissipation with an extended plastic hinge region. Among all CFFT columns, the hybrid lay-up demonstrated the highest flexural strength and initial stiffness, mainly because of its high reinforcement index and FRP/concrete stiffness ratio, respectively. Moreover, at the same drift ratio, the hybrid lay-up was also considered as the best in term of energy dissipation. Specimens with glassfiber tubes, on the other hand, exhibited the highest ductility due to better flexibility of glass FRP composites. Furthermore, ductility of CFFTs showed a strong correlation with the rupture strain of FRP. Parametric study further showed that different FRP architecture and rebar types may lead to different failure modes for CFFT columns. Transient analysis of strong ground motions showed that the column with off-axis nonlinear filament-wound glass FRP tube exhibited a superior seismic performance to all other CFFTs. Moreover, higher FRP reinforcement ratios may lead to a brittle system failure, while a well-engineered FRP reinforcement configuration may significantly enhance the seismic performance of CFFT columns.