Hydrophilic peptides derived from the transframe region of Gag-Pol inhibit the HIV-1 protease

The HIV-1 transframe region (TFR) is between the structural and functional domains of the Gag-Pol polyprotein, flanked by the nucleocapsid and the protease domains at its N and C termini, respectively. Transframe octapeptide (TFP) Phe-Leu-Arg-Glu-Asp-Leu-Ala-Phe, the N terminus of TFR, and its analogues are competitive inhibitors of the action of the mature HIV-1 protease. The smallest, most potent analogues are tripeptides: Glu-Asp-Leu and Glu-Asp-Phe with Ki values of approximately 50 and approximately 20 microM, respectively. Substitution of the acidic amino acids in the TFP by neutral amino acids and d or retro-d configurations of Glu-Asp-Leu results in an >40-fold increase in Ki. Protease inhibition by Glu-Asp-Leu is dependent on a protonated form of a group with a pKa of 3.8; unlike other inhibitors of HIV-1 protease which are highly hydrophobic, Glu-Asp-Leu is extremely soluble in water, and its binding affinity decreases with increasing NaCl concentration. However, Glu-Asp-Leu is a poor inhibitor (Ki approximately 7.5 mM) of the mammalian aspartic acid protease pepsin. X-ray crystallographic studies at pH 4.2 show that the interactions of Glu at P2 and Leu at P1 of Glu-Asp-Leu with residues of the active site of HIV-1 protease are similar to those of other product-enzyme complexes. It was not feasible to understand the interaction of intact TFP with HIV-1 protease under conditions of crystal growth due to its hydrolysis giving rise to two products. The sequence-specific, selective inhibition of the HIV-1 protease by the viral TFP suggests a role for TFP in regulating protease function during HIV-1 replication.     

Caring for dying children: nurses' experiences

Interviews with 25 nurses in this grounded theory study show that when nurses recognized that a child's death was inevitable, they struggled with both grief distress and moral distress. Their distress occurred within the context of the nurse-patient relationship. Nurses employed a range of strategies to manage their distress. Several conditions facilitated or constrained nurses' strategies, and resulted in far-reaching implications both professionally and personally.     

Cardiac autonomic dysfunction in survivors of acute lymphoblastic leukemia in childhood

Lower levels of baseline ventilatory function have consistently been associated with increased risk of cardiovascular mortality in prospective studies, but the underlying mechanisms are not known. Increased risk of coronary heart disease is associated with higher serum insulin levels. This report examines the relationship between ventilatory function and indirect measures of insulin resistance. Cross-sectional data from 922 nondiabetic participants in the Normative Aging Study were analysed using multiple linear regression models with adjustment for potential confounders. Forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) were examined in relation to indicators of insulin resistance, i.e. fasting insulin and the fasting insulin resistance index (FIRI). Diabetics were excluded because impaired insulin secretion interferes with the validity of these as measures of insulin resistance. Fasting insulin and FIRI were negatively correlated with FVC and FEV1 (all p< 0.001). These associations persisted after adjusting for potential confounders including age, height, body mass index, waist to hip circumference ratio, physical activity, alcohol intake and smoking in separate multiple linear regression models, for both insulin (all p< or =0.0008) and FIRI (all p< or =0.0001). Negative cross-sectional associations between ventilatory function and indirect measures of insulin resistance were found in nondiabetic males. Insulin resistance may contribute to the previously unexplained association between ventilatory function impairment and cardiovascular mortality. Mechanisms underlying the relationship between insulin resistance and decreased ventilatory function remain to be elucidated.     

Effect of precipitate type and morphology on high-temperature creep and internal stress in Al-Li based alloys

The tensile creep of a series of aluminium-lithium-based alloys, two binary alloys containing precipitate, and the 2090 alloy containing and T₁ precipitate, has been studied over a range of stresses at 150°C. In some cases the internal stress developed during creep has been determined using the strain transient dip test. The results have been compared with similar data previously obtained for the 8090 alloy containing and S precipitates. The solid solution alloy and the binary alloy containing shearable particles exhibited normal Class II behaviour, with the development of sub-grains and a stress dependence of the creep rate given by a single stress exponent,n, between 4 and 5 at all applied stresses. The alloys containing particles not easily sheared by dislocations, coarse , S and T₁, exhibited similar stress dependencies of the creep rate at low stresses but exhibited large values ofn, between 18 and 35 at high stresses. The internal stress, _i, in these alloys was found to be approximately constant at high stresses possibly due to partial shearing of the coarse , T₁, and the S on sub-boundaries. The stress dependence of the minimum creep rate, , could be represented at all applied stresses, _a, by , where (_a–_i) is the effective stress driving dislocations during creep, andn is a single stress exponent of between 5 and 6 for all applied stresses. The internal stress, which increases with applied stress, at least at a low applied stress, arises from inhomogeneity of plastic deformation, due to hard sub-boundaries or hard particles which are Orowan looped. These two types of contribution to the internal stress are of similar magnitude in the alloys containing coarse and T₁ but the majority of the internal stress in the 8090 alloy may arise as a result of the hardening of sub-boundaries by the S precipitate.     

Annexin 1 Is a Component of eATP-Induced Cytosolic Calcium Elevation in Arabidopsis thaliana Roots

Extracellular ATP (eATP) has long been established in animals as an important signalling molecule but this is less understood in plants. The identification of Arabidopsis thaliana DORN1 (Does Not Respond to Nucleotides) as the first plant eATP receptor has shown that it is fundamental to the elevation of cytosolic free Ca²⁺ ([Ca²⁺]_cyt) as a possible second messenger. eATP causes other downstream responses such as increase in reactive oxygen species (ROS) and nitric oxide, plus changes in gene expression. The plasma membrane Ca²⁺ influx channels involved in eATP-induced [Ca²⁺]_cyt increase remain unknown at the genetic level. Arabidopsis thaliana Annexin 1 has been found to mediate ROS-activated Ca²⁺ influx in root epidermis, consistent with its operating as a transport pathway. In this study, the loss of function Annexin 1 mutant was found to have impaired [Ca²⁺]_cyt elevation in roots in response to eATP or eADP. Additionally, this annexin was implicated in modulating eATP-induced intracellular ROS accumulation in roots as well as expression of eATP-responsive genes.     

On The Measurement of Temperature in Material Removal Processes

Because it is key to understanding the performance of material removal processes and resultant workpiece quality, the measurement of temperature during material removal is done extensively. We review several widely used temperature measurement methods and show how they can be applied to temperature monitoring during material removal. Since there is little documentation on measurement uncertainties as relates to material removal, this paper outlines the physics of each method, detailing the sources and evaluation of uncertainty. Finally, using criteria critical in measuring material removal, methods are compared, and the results presented in guide-format for participants in this field of work.     

The effect of protein binding on ibuprofen adsorption to activated carbons

The potential of a range of polymer-based activated carbons to remove a non-steroidal anti-inflammatory drug ibuprofen from protein containing and protein-free solutions was studied. The adsorption capacity of five activated carbons produced from phenol-formaldehyde resin precursors (MAST Carbon Ltd) was compared to a cellulose coated activated carbon Norit RBX used in a commercial Adsorba^®300C haemoperfusion column (Gambro).Ibuprofen adsorption was studied in batch experiments over 24 h at pH=7.6 and 25 °C and adsorption equilibrium data were correlated with the Langmuir and Freundlich equations.Results showed that uncoated mesoporous MAST carbons can remove ibuprofen from model solutions both in the presence and absence of serum albumin. Ibuprofen is a highly protein-bound drug and the presence of serum albumin significantly affects the adsorption of ibuprofen by cellulose-coated microporous carbon used in Adsorba^®300C column.     

Avalanching flow of cohesive powders

The flow dynamics of cohesive powders is investigated in rotating cylinders with an L : R ratio of 3 : 1 using experiments and DEM simulations. Flow onset and steady-state behavior are compared for free-flowing (cohesionless) dry glass beads, wet glass beads, and “dry” cohesive powders (lactose, microcrystalline cellulose). The avalanching dynamics of powders is substantially different from those observed for free-flowing or wet-cohesive glass beads. Dry cohesive powders exhibit history-dependent flow dynamics, significant dilation, aperiodic avalanche frequencies, and variable avalanche size. These behaviors also provide a route for effective characterization of cohesive forces under dilated conditions characteristic of unconfined flows.     

Factors influencing the photofading of commercial anthraquinone dyes in solution

The photofading of two anthraquinone dyes has been studied in aqueous solution using ultraviolet-visible absorption spectroscopy and flash photolysis. The influence of alcohol concentration, pH, atmosphere, photosensitisers and stabilisers have been examined and these lead to some important conclusions on the mechanism of dye fading. Essentially, the results indicate the photoexcited triplet state of the dye undergoes a process of either electron or hydrogen-atom abstraction depending on the nature of the environment. Other factors such as aggregation and singlet oxygen also appear to play an important role in solution photofading. The relevance of these results to photofading in a polymeric phase is discussed.