Structure of CC Chemokine Receptor 5 with a Potent Chemokine Antagonist Reveals Mechanisms of Chemokine Recognition and Molecular Mimicry by HIV.

CCR5 is the primary chemokine receptor utilized by HIV to infect leukocytes, whereas CCR5 ligands inhibit infection by blocking CCR5 engagement with HIV gp120. To guide the design of improved therapeutics, we solved the structure of CCR5 in complex with chemokine antagonist [5P7]CCL5. Several structural features appeared to contribute to the anti-HIV potency of [5P7]CCL5, including the distinct chemokine orientation relative to the receptor, the near-complete occupancy of the receptor binding pocket, the dense network of intermolecular hydrogen bonds, and the similarity of binding determinants with the FDA-approved HIV inhibitor Maraviroc. Molecular modeling indicated that HIV gp120 mimicked the chemokine interaction with CCR5, providing an explanation for the ability of CCR5 to recognize diverse ligands and gp120 variants. Our findings reveal that structural plasticity facilitates receptor-chemokine specificity and enables exploitation by HIV, and provide insight into the design of small molecule and protein inhibitors for HIV and other CCR5-mediated diseases.

Experimental and numerical study on Cu and Cd migration in different functional-area soils under simulated rainfall conditions.

Natural rainfall exerts a significant influence on the migration of heavy metals in soil. However, the knowledge of migration characteristics and release kinetics of heavy metals in contaminated soils under different rainfall intensities still remains unclear. In this study, the simulated rainfall of different intensities was designed to experimentally and numerically investigate Cu and Cd movements in different functional-area (agriculture, industrial, urban) soils. A HYDRUS-2D model was optimized to simulate the migration process of Cu and Cd in soil under different rainfall conditions. The hydraulic properties and solute transport parameters used in the model were estimated based on isothermal adsorption and chloride ion penetration experimental measurements and related model fitting. Furthermore, Cu and Cd BTCs (Breakthrough Curves) were fitted using the HYDRUS-2D inverse solution function with two-site model. The results showed that the order of the migration capacity of Cu and Cd in different functional-area soils was agriculture soil > industrial soil > urban soil, and Cd had a greater risk of groundwater pollution than Cu. With the increase of rainfall intensity, the high proportion of the exchangeable state of Cu and Cd in contaminated soil is easy to be released. Furthermore, the model was proved to describe the distribution of Cu and Cd in the soil profile very well. The present results can improve understanding of the environmental behavior of Cu and Cd in different functional-areas soils and can be used as a basis for risk assessment of Cu and Cd polluting groundwater.

Further characterization of distinct high-affinity binding sites for dinotefuran in the abdominal nerve cord of the American cockroach Periplaneta americana (Blattodea).

Dinotefuran (DTF) is a systemic neonicotinoid insecticide characterized by a tetrahydrofuran ring. In the present study, we examined the characteristics of DTF binding to native nicotinic acetylcholine receptors (nAChRs) expressed in the American cockroach Periplaneta americana using radioligand-binding methods. The Scatchard analysis, using [3H]imidacloprid (IMI), indicated that IMI has a single class of high-affinity binding sites in the P. americana nerve cord. In contrast, the Scatchard analysis using [3H]DTF indicated that DTF has two different classes of binding sites. Both DTF and IMI were found to bind to one of the classes, for which DTF showed low affinity. The other class, for which DTF showed high affinity, was localized in the abdominal nerve cord but not in the thoracic nerve cord. IMI showed low affinity for the high-affinity DTF binding sites. Our data suggest that DTF binds with high affinity to a nAChR subtype distinct from the high-affinity subtype for IMI. This difference might be responsible, at least in part, for the difference in resistance development to DTF and IMI in P. americana.

Sorption and leaching potential of organophosphorus insecticide dimethoate in Croatian agricultural soils.

Dimethoate is an organophosphorus insecticide still used in Croatia and worldwide, with polar structure and high water solubility that make it prone to leaching. This study analyzed how physico-chemical properties of soils affected dimethoate sorption and mobility. For that purpose, five soil samples were collected from three Croatian regions (two coastal and one mountain region). Dimethoate sorption process was analyzed using the batch procedure while its mobility and leaching potential was investigated by column experiment. The results showed that dimethoate sorption can be adequately described by Freundlich model. All isotherms were of L-type with varying degrees of non-linearity, indicating different sorption efficiencies and distribution of sorption sites energies among the soils. Energy distribution was broader in soils richer in organic matter (OM). KF values indicated relatively low sorption efficiency for all soils, with an increase of KF values proportional to OM content. Mechanisms involved in dimethoate sorption and mobility were analyzed by fitting the breakthrough curves (BTCs) with two mathematical models, namely one-site equilibrium (ELM) and two-site nonequilibrium sorption model (NELM). Correlations were quantified by Kendall-Tau test, which revealed the strongest correlation of KF value with OM content, cation exchange capacity and the humic acid content, while correlations with pH, clay content and A465nm/A665nm ratio were negative and insignificant. Based on these findings, a model for prediction of leaching potential was formed. A simplified model for dimethoate sorption/transport was proposed.

Adsorption and desorption for dynamics transport of hexavalent chromium (Cr(VI)) in soil column.

Batch experiments have been carried out to study the adsorption of heavy metals in soils, and the migration and transformation of hexavalent chromium (Cr(VI)) in the soil of a vegetable base were studied by dynamic adsorption and desorption soil column experiments. The aim of this study was to investigate the effect of initial concentration and pH value on the adsorption process of Cr(VI). Breakthrough curve were used to evaluate the capacity of Cr(VI) adsorption in soil columns. The results show that the higher the initial concentration, the worse the adsorption capacity of Cr(VI). The adsorption of Cr(VI) was strongly sensitive to pH value. The capacity of Cr(VI) adsorption is maximized at very low pH value. This may be due to changes in pH that cause a series of complex reactions in Cr(VI). In a strongly acidic environment, the reaction of Cr(VI) with hydrogen ions is accompanied by the formation of Cr3+, which reacts with the soil free iron-aluminum oxide to produce hydroxide in the soil. The results of the desorption experiments indicate that Cr(VI) is more likely to leach from this soil, but if the eluent is a strong acid solution, the leaching process will be slow and persistent. During the experiment, the pH value of the effluent was in the range of 7-8.5, which tends to the original pH value of the soil. It is indicating that the soil has a strong buffer on the acid liquid. The program CXTFIT was used to fit the breakthrough curve to estimate parameters. The results of the calculation of the dispersion coefficient (D) can be obtained by this program. The two-site model fit the breakthrough curve data of Cr(VI) well, and the parameters calculated by the CXTFIT can be used to explain the behavior of Cr(VI) migration and transformation in soil columns. When pH = 2, the retardation factor (R) reach at 79.71 while the value of the R is generally around 10 in other experiments. The partitioning coefficient ß shows that more than half of the adsorption sites are instantaneous in this adsorption process and non-equilibrium affects the Cr(VI) transport process in this soil.

New paradigms in chemokine receptor signal transduction: Moving beyond the two-site model.

Chemokine receptor (CKR) signaling forms the basis of essential immune cellular functions, and dysregulated CKR signaling underpins numerous disease processes of the immune system and beyond. CKRs, which belong to the seven transmembrane domain receptor (7TMR) superfamily, initiate signaling upon binding of endogenous, secreted chemokine ligands. Chemokine-CKR interactions are traditionally described by a two-step/two-site mechanism, in which the CKR N-terminus recognizes the chemokine globular core (i.e. site 1 interaction), followed by activation when the unstructured chemokine N-terminus is inserted into the receptor TM bundle (i.e. site 2 interaction). Several recent studies challenge the structural independence of sites 1 and 2 by demonstrating physical and allosteric links between these supposedly separate sites. Others contest the functional independence of these sites, identifying nuanced roles for site 1 and other interactions in CKR activation. These developments emerge within a rapidly changing landscape in which CKR signaling is influenced by receptor PTMs, chemokine and CKR dimerization, and endogenous non-chemokine ligands. Simultaneous advances in the structural and functional characterization of 7TMR biased signaling have altered how we understand promiscuous chemokine-CKR interactions. In this review, we explore new paradigms in CKR signal transduction by considering studies that depict a more intricate architecture governing the consequences of chemokine-CKR interactions.

The Decay of Disease Association with Declining Linkage Disequilibrium: A Fine Mapping Theorem.

Several important and fundamental aspects of disease genetics models have yet to be described. One such property is the relationship of disease association statistics at a marker site closely linked to a disease causing site. A complete description of this two-locus system is of particular importance to experimental efforts to fine map association signals for complex diseases. Here, we present a simple relationship between disease association statistics and the decline of linkage disequilibrium from a causal site. Specifically, the ratio of Chi-square disease association statistics at a marker site and causal site is equivalent to the standard measure of pairwise linkage disequilibrium, r2. A complete derivation of this relationship from a general disease model is shown. Quite interestingly, this relationship holds across all modes of inheritance. Extensive Monte Carlo simulations using a disease genetics model applied to chromosomes subjected to a standard model of recombination are employed to better understand the variation around this fine mapping theorem due to sampling effects. We also use this relationship to provide a framework for estimating properties of a non-interrogated causal site using data at closely linked markers. Lastly, we apply this way of examining association data from high-density genotyping in a large, publicly-available data set investigating extreme BMI. We anticipate that understanding the patterns of disease association decay with declining linkage disequilibrium from a causal site will enable more powerful fine mapping methods and provide new avenues for identifying causal sites/genes from fine-mapping studies.