Fast and one-step folding of closely and distantly related homologous proteins of a four-helix bundle family

Bovine acyl-coenzyme A binding protein is a four-helix bundle protein belonging to a group of homologous eukaryote proteins that binds medium and long-chain acyl-coenzyme A esters with a very high affinity. The three-dimensional structure of both the free and the ligated protein together with the folding kinetics have been described in detail for the bovine protein and with four new sequences reported here, a total of 16 closely related sequences ranging from yeasts and plants to human are known. The kinetics of folding and unfolding in different concentrations of guanidine hydrochloride together with equilibrium unfolding have been measured for bovine, rat and yeast acyl-coenzyme A binding protein. The bovine and rat sequences are closely related whereas the yeast is more distantly related to these. In addition to the three natural variants, kinetics of a bovine mutant protein, Tyr31 --> Asn, have been studied. Both the folding and unfolding rates in water of the yeast protein are 15 times faster than those of bovine. The folding rates in water of the two mammalian forms, rat and bovine, are similar, though still significantly different. A faster unfolding rate both for rat and the bovine mutant protein results from a lower stability of the native states of these. These hydrophobic regions, mini cores, have been identified in the three-dimensional structure of the bovine protein and found to be formed primarily by residues that have been conserved throughout the entire eukaryote evolution from yeasts to both plants and mammals as seen in the sample of 16 sequences. The conserved residues are found to stabilize helix-helix interactions and serve specific functional purposes for ligand binding. The fast one-step folding mechanism of ACBP has been shown to be a feature that seems to be maintained throughout evolution despite numerous differences in sequence and even dramatic differences in folding kinetics and protein stability. The protein study raises the question to what extent does the conserved hydrophobic residues provide a scaffold for an efficient one-step folding mechanism.     

Optimization of signal detection in SPECT

Parallel-hole collimators of varying design are discussed, using the display signal-to-noise ratio of R.F. Wagner et al. (Med. Phys., vol.6, p.83-94, 1979) to obtain contrast-detail diagrams and analytical expressions for the signal-to-noise ratio in SPECT (single-photon-emission computed tomography). It is concluded: (1) that the detectability of deeply embedded small objects (more than ~10 cm deep) may be improved only slightly by improvements in the resolution and geometric efficiency of parallel-hole collimators; (2) that a long-bore collimator outperforms a low-energy general-purpose collimator for objects smaller than ~2 cm, but only to a minor degree; and (3) that for improvement of small object detectability by SPECT, the most fruitful technological pursuit would probably involve development of focused collimators.     

Future directions and research issues for ergonomics and advanced manufacturing technology (AMT)

In recent years, great progress has been made in the development of computer-based technologies that support the manufacturing industries. Those concerned with advanced manufacturing technology (AMT) are becoming increasingly aware of the fundamental importance of human organisational issues for the successful development, implementation, operation and maintenance of AMT. The discipline of industrial ergonomics and occupational occupational psychology, therefore, have a significant contribution to make in this field. This paper introduces the special issue, Ergonomics Matters in AMT, and presents a discussion of some of the future directions of AMT and the likely implications for ergonomics research.     

Mobility degradation effects in CMOS differential pair transconductors

The influence of the mobility reduction factor on the dominant third-harmonic distortion and effective transconductance in CMOS differential pair transconductors is examined. Analytical expressions are developed which are suitable for hand calculation and generate realistic estimates for distortion and transconductance. The results produced have been tested against SPICE simulations over a wide range of parameter values and show excellent agreement. The analysis highlights the importance of mobility degradation and reveals that the linearity of the source-coupled differential pair is actually improved as the mobility reduction factor increases. This surprising finding suggests that where 0.15, for example, acceptably low distortion levels (<60 dB for V _i =1 V _pp ) should be achievable with the basic long-tailed pair and that complex linearization schemes may be unnecessary.This work is supported by a grant of the Science and Engineering Research Council.     

Experimental results of the erosion of molybdenum due to blistering by He+ bombardment

We report some preliminary measurement of the erosion rate of plasma dumps when bombarded with 100 keV He⁺ ions at high power density ( 1 MW/m²). The expected erosion rates, based on measurements of He blistering that were made at lower power density ( 0.3 MW/m²), indicate a potentially serious problem for fusion reactors. Our tests use a reactorlike power density and produce He blisters at a rate that is slower than predicted by 2 to 4 orders of magnitude, depending on the temperature of the molybdenum target.     

The behavior of small fatigue cracks at notches in corrosive environments

The behavior of small cracks growing out of the roots of blunt notches in compact type specimens of an austenitic steel was characterized under fatigue loading in wet H ₂ plus air environment. The growth rates of cracks in the size range of 0.125 mm to 0.75 mm were up to two orders of magnitude higher than the rates expected for conventional cracks at equal stress intensity range, K. It was also observed that the small cracks grew at these fast rates only in corrosive environments when the loading frequency was 0.02 Hz or less. At a frequency of 10 Hz, the behavior was in agreement with the trend predicted for conventional size cracks.The above observations are rationalized in terms of the breakdown of the concept of a single parameter representation of the crack tip stress and strain field by K or in terms of differences in crack tip environments between small and long cracks for the same bulk environment. A simple engineering model is proposed which adequately represents the observed small crack growth behavior.

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Résumé On a procédé à la caractérisation, sous charges de fatigue en atmosphère humide de H ₂ et d'air, de petites fissures se développant à partir des racines d'entailles arrondies dans des éprouvettes compactes.Les vitesses de croissance des fissures d'une taille allant de 0,125 à 0,750 mm se sont révélé être de deux ordres de grandeur plus grandes que les vitesses prévues dans le cas de fissures conventionnelle, soumises aux mêmes variations de l'intensité de contrainte K. On a également observé que de petites fissures croissaient à ces grandes vitesses seulement dans des atmosphères corrosives, lorsque la fréquence de sollicitation était de 0,02 Hz ou moins. A la fréquence de 10 Hz, le comportement observé s'est trouvé en accord avec les tendances prévues pour des fissures de taille conventionnelle.Les observations ci-dessus sont rationnalisées en un élargissement du concept de représentation monoparamétrique par le facteur K du champ de contraintes et de dilatation à l'extrémité de la fissure, ou en termes des différences rencontrées dans l'environnement local de l'extrémité d'une fissure, selon que celle-ci est longue ou courte, et ce dans un même environnement global.On propose un modèle simple utilisable en pratique, pour représenter de manière adéquate le comportement à la croissance observé pour des petites fissures.

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Metallurgy Department     

RelativizedNC

This paper introduces a notion of relativized depth for circuit families and discusses issues regarding uniform families of relativized circuits. This allows us to define a version of relativizedNC and compare it under various oracles with relativizedL, NL, andP. We see thatNC ₁ is properly contained inL if and only if there exists an oracleA such thatNC ₁ ^A is properly contained inL ^A . There is an oracleA where the hierarchy collapses,NC ₁ ^A = NC ^A , and another whereNC ₁ ^A NC ₂ ^A NC ^A P ^A . We then construct anA so that, for anyk, NC ₁ ^A contains a set not inNSPACE ^A (O(n ^k )), suggesting that the notion of relativized space is too weak or that of relativized depth is too strong.     

The Effects of Insulin-Like Growth Factor I and BTP-2 on Acute Lung Injury

Acute lung injury (ALI) afflicts approximately 200,000 patients annually and has a 40% mortality rate. The COVID-19 pandemic has massively increased the rate of ALI incidence. The pathogenesis of ALI involves tissue damage from invading microbes and, in severe cases, the overexpression of inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). This study aimed to develop a therapy to normalize the excess production of inflammatory cytokines and promote tissue repair in the lipopolysaccharide (LPS)-induced ALI. Based on our previous studies, we tested the insulin-like growth factor I (IGF-I) and BTP-2 therapies. IGF-I was selected, because we and others have shown that elevated inflammatory cytokines suppress the expression of growth hormone receptors in the liver, leading to a decrease in the circulating IGF-I. IGF-I is a growth factor that increases vascular protection, enhances tissue repair, and decreases pro-inflammatory cytokines. It is also required to produce anti-inflammatory 1,25-dihydroxyvitamin D. BTP-2, an inhibitor of cytosolic calcium, was used to suppress the LPS-induced increase in cytosolic calcium, which otherwise leads to an increase in proinflammatory cytokines. We showed that LPS increased the expression of the primary inflammatory mediators such as toll like receptor-4 (TLR-4), IL-1β, interleukin-17 (IL-17), TNF-α, and interferon-γ (IFN-γ), which were normalized by the IGF-I + BTP-2 dual therapy in the lungs, along with improved vascular gene expression markers. The histologic lung injury score was markedly elevated by LPS and reduced to normal by the combination therapy. In conclusion, the LPS-induced increases in inflammatory cytokines, vascular injuries, and lung injuries were all improved by IGF-I + BTP-2 combination therapy.     

Experiment and simulation study of 3D magnetic field sensing for magnetic flux leakage defect characterisation

Magnetic flux leakage (MFL) testing is widely used to detect and characterise defects in pipelines, rail tracks and other structures. The measurement of the two field components perpendicular to the test surface and parallel to the applied field in MFL systems is well established. However, it is rarely effective when the shapes of the specimens and defects with respect to the applied field are arbitrary. In order to overcome the pitfalls of traditional MFL measurement, measurement of the three-dimensional (3D) magnetic field is proposed. The study is undertaken using extensive finite element analysis (FEA) focussing on the 3D distribution of magnetic fields for defect characterisation and employing a high sensitivity 3-axis magnetic field sensor in experimental study. Several MFL tests were undertaken on steel samples, including a section of rail track. The experimental and FEA test results show that data from not only the x- and z-axes but also y-axis can give comprehensive positional information about defects in terms of shape and orientation, being especially advantageous where the defect is aligned close to parallel to the applied field. The work concludes that 3D magnetic field sensing could be used to improve the defect characterisation capabilities of existing MFL systems, especially where defects have irregular geometries.