Redox-Linked Domain Movements in the Catalytic Cycle of Cytochrome P450 Reductase

SummaryNADPH-cytochrome P450 reductase is a key component of the P450 mono-oxygenase drug-metabolizing system. There is evidence for a conformational equilibrium involving large-scale domain motions in this enzyme. We now show, using small-angle X-ray scattering (SAXS) and small-angle neutron scattering, that delivery of two electrons to cytochrome P450 reductase leads to a shift in this equilibrium from a compact form, similar to the crystal structure, toward an extended form, while coenzyme binding favors the compact form. We present a model for the extended form of the enzyme based on nuclear magnetic resonance and SAXS data. Using the effects of changes in solution conditions and of site-directed mutagenesis, we demonstrate that the conversion to the extended form leads to an enhanced ability to transfer electrons to cytochrome c. This structural evidence shows that domain motion is linked closely to the individual steps of the catalytic cycle of cytochrome P450 reductase, and we propose a mechanism for this

The relationships between bone mineral density in the spine, hip, distal femur and proximal tibia and medial minimum joint space width in the knees of healthy females

SummaryObjectiveTo investigate the relationships between bone mineral density (BMD) in the hip, spine, distal femur and proximal tibia and minimum joint space width (mJSW) in the knees of healthy women.MethodsWomen 22–68 years old without a history of knee pain, bone or joint disease or injury underwent a single, fixed-flexion knee X-ray. Radiographs were graded according to the Kellgren–Lawrence scale and analyzed for mJSW using a computer algorithm. Dual X-ray absorptiometry scans of the spine, hip, distal femur and proximal tibia were also acquired for each participant. Femur and tibia scans were acquired and analyzed using a modified version of the lumbar spine software.ResultsForty-five females, mean [standard deviation (SD)] age and body mass index (BMI) of 40.1 (13.9) years and 24.6 (4.5)kg/m2, respectively, participated. The mean (SD) mJSW was 4.64 (0.68)mm. Linear regression analyses controlling for age and BMI revealed that BMD in the femoral trochanter and the central two regions of the tibia (T2 and T3) was significantly related to mJSW in the knee. A backwards regression analysis performed to determine which region of interest is most significantly related to mJSW revealed that femoral trochanter BMD (β-value=0.416) is the most significant.ConclusionsIn contrast to the suggestion that BMD is negatively correlated with mJSW in the knees of osteoarthritic individuals, these results suggest that increasing BMD in the femoral trochanter and tibia is significantly associated with increasing mJSW in healthy females. Further investigation of this relationship is warranted

REACHING THE "ATTENTIVE PUBLIC" WITH DISCUSSION GROUP FACT SHEETS

Teaching/Communication/Extension/Profession,

Risk of incident dementia and cognitive impairment in patients with chronic obstructive pulmonary disease (COPD): A large UK population-based study

Background: Although cognitive impairment and dementia are common comorbidities in patients with chronic obstructive pulmonary disease (COPD), estimates of incidence following a diagnosis of COPD are inconclusive. Objective: To determine the incidence of cognitive impairment and dementia in people with and without a COPD diagnosis. Methods: A population-based study using UK General Practice (GP) health records from The Health Improvement Network database was conducted. Patients with confirmed COPD diagnosis, ≥40 years old, were matched to up to four subjects without a COPD diagnosis by age, sex and GP practice. Cox proportional hazards models were used to assess the incidence rates of cognitive impairment and dementia. Results: Of patients with COPD (n = 62,148), 9% developed cognitive impairment, compared with 7% of subjects without COPD (n = 230,076), p < 0.001. The incidence of cognitive impairment following COPD diagnosis was greater than in subjects without COPD following index date (adjusted Hazard Ratio (aHR), 1.21; 95% CI: 1.16 ─ 1.26, p < 0.001). The coded incidence of either cognitive impairment or dementia was also greater in patients with COPD following adjustment for confounders (aHR: 1.13, 95% CI: 1.09 ─ 1.18, p < 0.001). Coded incident dementia alone was not different between patients with COPD and subjects without COPD (aHR, 0.91, 95% CI: 0.83 ─ 1.01, p = 0.053). Conclusion: Despite the increased incidence of cognitive impairment in patients with COPD, incidence of dementia was not as frequently recorded in patients with COPD. This raises the concern of undiagnosed dementia and emphasises the need for a systematic assessment in this population

Structure and Functional Evaluation of Tendon–Skeletal Muscle Constructs Engineered in Vitro

During muscle contraction, the integrity of the myotendinous junction (MTJ) is important for the transmission of force from muscle to tendon. We evaluated the contractile and structural characteristics of 3-dimensional (3-D) skeletal muscle constructs co-cultured with engineered self-organized tendon constructs (n = 4), or segments of adult (n = 4) or fetal (n = 5) rat-tail tendon. We hypothesized that the co-culture of tendon and muscle would produce constructs with viable muscle–tendon interfaces that remain intact during generation of force. Construct diameter (lm) and maximum isometric force (µN) were measured, and specific force (kPa) was determined. After measure of force, constructs were loaded at a constant strain rate until failure and surface strains were recorded optically across the tendon, the muscle and the interface and used to determine the tangent modulus (passive stiffness) of the construct. Frozen samples were used for Trichrome Masson staining and immunofluorescent analysis of the MTJ-specific protein paxillin. No differences were observed between the groups with respect to diameter, maximum force, or specific force. The MTJ was robust and withstood tensile loading beyond the physiological strain range. The majority of the constructs failed in the muscle region. At the MTJ, there is an increase in the expression and localization of paxillin. In conclusion, using 3 sources of tendon tissue, we successfully engineered 3-D muscle–tendon constructs with functionally viable MTJ, characterized by structural features and protein expression patterns resembling neonatal MTJs in vivo.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63387/1/ten.2006.12.3149.pd

Entanglement Sudden Death in Band Gaps

Using the pseudomode method, we evaluate exactly time-dependent entanglement for two independent qubits, each coupled to a non-Markovian structured environment. Our results suggest a possible way to control entanglement sudden death by modifying the qubit-pseudomode detuning and the spectrum of the reservoirs. Particularly, in environments structured by a model of a density-of-states gap which has two poles, entanglement trapping and prevention of entanglement sudden death occur in the weak-coupling regime

Coupled Dipole Method Determination of the Electromagnetic Force on a Particle over a Flat Dielectric Substrate

We present a theory to compute the force due to light upon a particle on a dielectric plane by the Coupled Dipole Method (CDM). We show that, with this procedure, two equivalent ways of analysis are possible, both based on Maxwell's stress tensor. The interest in using this method is that the nature and size or shape of the object, can be arbitrary. Even more, the presence of a substrate can be incorporated. To validate our theory, we present an analytical expression of the force due to the light acting on a particle either in presence, or not, of a surface. The plane wave illuminating the sphere can be either propagating or evanescent. Both two and three dimensional calculations are studied.Comment: 10 pages, 8 figures and 3 table

SNP associations and genetic-parameter estimation for nose and hoof pigmentation in Corriedale sheep

Published Online 7/6/23 OnlinePublContext. Quantity and quality of both meat and wool are important for selection programs of the dual-purpose Corriedale sheep. In Corriedales, black pigmentation of nose skin and hooves is preferred as part of the breed standard. However, within the breed, pigmentation can vary from none to complete pigmentation. Aims. The aim was to discover single-nucleotide polymorphisms (SNPs) and genes associated with nose and hoof pigmentation and to estimate genetic parameters of nose and hoof pigmentation, wool traits and meat traits. Methods. The phenotype and genotype data on Corriedale lambs (n = 764) produced from 44 sires (12 studs) and 300 ewes in 2017–2019 were used in this study. Lambs were slaughtered at 6–7 months of age. Nose pigmentation and hoof pigmentation were scored on a five-point scale, where no pigmentation was scored 0 and complete pigmentation was scored 5. Wool-and meat-quality traits were measured, including greasy fleece weight, fibre diameter, weaning weight, hot standard carcass weight and intramuscular fat percentage. The lambs were genotyped with the GGPOvine50K SNP chip. A genome-wide association study (GWAS) was conducted. Genetic parameters and bivariate analyses were estimated using ASReml-R. Results. The lambs had a mean nose-pigmentation score of 3.69 and hoof-pigmentation score of 4.12. The nose pigmentation (h2 = 0.58) and hoof pigmentation (h2 = 0.51) were highly heritable and highly correlated (rG = 0.73). The GWAS identified a genome-wide significant SNP (OAR19_33278780.1) associated with nose pigmentation (q-value = 0.04). This SNP is positioned in a known pigmentation gene, melanocyte-inducing transcription factor (MITF ). The same SNP was the sixth-most associated SNP for hoof pigmentation but did not reach significance level. OAR19_33278780.1 also had a significant effect on back conformation and weaning weight. Conclusions. The results of these analyses have provided information and an understanding of the genetics for pigmentation of nose and hooves in Corriedale sheep. Implications. Nose and hoof pigmentation are highly genetically correlated with each other, but with no negative effects on production traits.J. E. Aldersey, M. S. Khatkar, P. J. Blackwood, C. E. Blackwood, J. M. Pitchford, H. Gordon, S. C. Welsh and W. S. Pitchfor

Schrodinger equation with a spatially and temporally random potential: Effects of cross-phase modulation in optical communication

We model the effects of cross-phase modulation in frequency (or wavelength) division multiplexed optical communications systems, using a Schrodinger equation with a spatially and temporally random potential. Green's functions for the propagation of light in this system are calculated using Feynman path-integral and diagrammatic techniques. This propagation leads to a non-Gaussian joint distribution of the input and output optical fields. We use these results to determine the amplitude and timing jitter of a signal pulse and to estimate the system capacity in analog communication

Small Water Bodies in Great Britain and Ireland: Ecosystem function, human-generated degradation, and options for restorative action

© 2018 Small, 1st and 2nd-order, headwater streams and ponds play essential roles in providing natural flood control, trapping sediments and contaminants, retaining nutrients, and maintaining biological diversity, which extend into downstream reaches, lakes and estuaries. However, the large geographic extent and high connectivity of these small water bodies with the surrounding terrestrial ecosystem makes them particularly vulnerable to growing land-use pressures and environmental change. The greatest pressure on the physical processes in these waters has been their extension and modification for agricultural and forestry drainage, resulting in highly modified discharge and temperature regimes that have implications for flood and drought control further downstream. The extensive length of the small stream network exposes rivers to a wide range of inputs, including nutrients, pesticides, heavy metals, sediment and emerging contaminants. Small water bodies have also been affected by invasions of non-native species, which along with the physical and chemical pressures, have affected most groups of organisms with consequent implications for the wider biodiversity within the catchment. Reducing the impacts and restoring the natural ecosystem function of these water bodies requires a three-tiered approach based on: restoration of channel hydromorphological dynamics; restoration and management of the riparian zone; and management of activities in the wider catchment that have both point-source and diffuse impacts. Such activities are expensive and so emphasis must be placed on integrated programmes that provide multiple benefits. Practical options need to be promoted through legislative regulation, financial incentives, markets for resource services and voluntary codes and actions