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Impacts from urban stormwater runoff on receiving environments have been well documented, particularly through specific regional scientific studies. Using various local government planning and management elements, urban developments in Brisbane City are now able to address stormwater management in an increasingly holistic context. One key initiative includes facilitating Water Sensitive Urban Design (WSUD) components within an Integrated Water Management Strategy that looks at policy formation, planning strategies, design option, community marketing and acceptance, maintenance programs and finally evaluation of various WSUD approaches. These can include the use of Natural Channel Designs, grassed swales, bio-filtration systems, porous pavements and roofwater tanks in several economic combinations. By linking with the Cooperative Research Centre for Catchment Hydrology, Brisbane City Council has influenced the design of WSUD planning tools and benefited the city with academic inputs into extensive evaluation programs. As well, it has also contributed to the Cooperative Research Centre's research outcomes. These evaluation programs are increasingly providing better understanding of various stormwater quality best management practices throughout Australia. As part of the overall implementation process, active involvement by a range of stakeholders has been crucial. These stakeholders have included internal planning, development assessment and design staff, external consultants, developers, and other local and state government agencies. The latter two groups are assisting in the important task of “regionalisation” of Brisbane City Council's policies and guidelines. Implementation of WSUD initiatives and stormwater re-use strategies under Council's new “Integrated Water Management” agenda are showing some excellent results, suggesting that sustainable urban development is no longer like the search for the Holy Grail. [ABSTRACT FROM AUTHOR]

Although female mating preferences are a focus of current controversy, little detailed information exists on female preferences within natural populations. In the field cricket Gryllus integer, male calls attract sexually receptive females, and females preferentially move toward male calls with longer calling bouts (periods of calling containing no pause greater than 0.10 s in real time). This study investigated female preferences for other variables of the male song, including syllable period, chirp pause, and number of syllables per chirp. Male song was measured in the field to determine mean values for each variable in nature. Female preferences were determined using a locomotor-compensator device, on which females ran in response to sequential playbacks of synthesized male song. Mean female preferences corresponded roughly to mean male song variables. Nonetheless, females varied greatly in their responses to synthesized calls differing in syllable period, syllable number, and chirp pause. Moreover, individual females who were more selective for any one variable also tended to be more selective for others. These results show that females may differ from one another in their mating preferences and degrees of selectivity, even within a single population. [ABSTRACT FROM AUTHOR]

Hypertension and heart failure are worldwide health problems of ever-increasing proportions. A failure of the heart, during either systolic and/or diastolic phases of the cardiac cycle, has its origins rooted in an adverse structural, biochemical, and molecular remodelling of myocardium that involves its cellular constituents, extracellular matrix, and intramural coronary vasculature. Herein we focus on the pathogenic role of a dyshomeostasis of several macro- (i.e. Ca2+ and Mg2+) and micronutrients (i.e. Zn2+, Se2+, and vitamin D) in contributing to adverse remodelling of the myocardium and its failure as a pulsatile muscular pump. An improved understanding of how these macro- and micronutrients account for the causes and consequences of adverse myocardial remodelling carries with it the potential of identifying new biomarkers predictive of risk, onset and progression, and response to intervention(s), which could be monitored non-invasively and serially over time. Moreover, such incremental knowledge will serve as the underpinning to the development of novel strategies aimed at preventing and/or regressing the ongoing adverse remodelling of myocardium. The time is at hand to recognize the importance of macro- and micronutrient dyshomeostasis in the evaluation and management of hypertension and heart failure. [ABSTRACT FROM AUTHOR]

HTLV-1 [HTLV (human T-cell lymphotrophic virus) type 1] is associated with a number of human diseases. HTLV-1 protease is essential for virus replication, and similarly to HIV-1 protease, it is a potential target for chemotherapy. The primary sequence of HTLV-1 protease is substantially longer compared with that of HIV-1 protease, and the role of the ten C-terminal residues is controversial. We have expressed C-terminally-truncated forms of HTLV-1 protease with and without N-terminal His tags. Removal of five of the C-terminal residues caused a 4–40-fold decrease in specificity constants, whereas the removal of an additional five C-terminal residues rendered the protease completely inactive. The addition of the N-terminal His tag dramatically decreased the activity of HTLV-1 protease forms. Pull-down experiments carried out with His-tagged forms, gel-filtration experiments and dimerization assays provided the first unequivocal experimental results for the role of the C-terminal residues in dimerization of the enzyme. There is a hydrophobic tunnel on the surface of HTLV-1 protease close to the C-terminal ends that is absent in the HIV-1 protease. This hydrophobic tunnel can accommodate the extra C-terminal residues of HTLV-1 protease, which was predicted to stabilize the dimer of the full-length enzyme and provides an alternative target site for protease inhibition. [ABSTRACT FROM AUTHOR]

Darunavir, a potent antiviral drug, showed an unusual second binding site on the HIV-1 protease dimer surface of the V32I drug resistant mutant and normal binding in the active site cavity. Kinetic analysis for wild type and mutant protease showed mixed-type competitive−uncompetitive inhibition for darunavir and the chemically related amprenavir, while saquinavir showed competitive inhibition. The inhibition model is consistent with the observed second binding site for darunavir and helps to explain its antiviral potency. [ABSTRACT FROM AUTHOR]

The extreme temperatures and nonthermal nature of the solar corona and solar wind arise from an unidentified physical mechanism that preferentially heats certain ion species relative to others. Spectroscopic indicators of unequal temperatures commence within a fraction of a solar radius above the surface of the Sun, but the outer reach of this mechanism has yet to be determined. Here we present an empirical procedure for combining interplanetary solar wind measurements and a modeled energy equation including Coulomb relaxation to solve for the typical outer boundary of this zone of preferential heating. Applied to two decades of observations by the Wind spacecraft, our results are consistent with preferential heating being active in a zone extending from the transition region in the lower corona to an outer boundary 20–40 solar radii from the Sun, producing a steady-state super-mass-proportional α-to-proton temperature ratio of 5.2–5.3. Preferential ion heating continues far beyond the transition region and is important for the evolution of both the outer corona and the solar wind. The outer boundary of this zone is well below the orbits of spacecraft at 1 au and even closer missions such as Helios and MESSENGER, meaning it is likely that no existing mission has directly observed intense preferential heating, just residual signatures. We predict that the Parker Solar Probe will be the first spacecraft with a perihelion sufficiently close to the Sun to pass through the outer boundary, enter the zone of preferential heating, and directly observe the physical mechanism in action. [ABSTRACT FROM AUTHOR]

We report the design, synthesis, biological evaluation, and the X-ray crystal structure of a novel inhibitor bound to the HIV-1 protease. Various C3-functionalized cyclopentanyltetrahydrofurans (Cp-THF) were designed to interact with the flap Gly48 carbonyl or amide NH in the S2-subsite of the HIV-1 protease. We investigated the potential of those functionalized ligands in combination with hydroxyethylsulfonamide isosteres. Inhibitor 26containing a 3-(R)-hydroxyl group on the Cp-THF core displayed the most potent enzyme inhibitory and antiviral activity. Our studies revealed a preference for the 3-(R)-configuration over the corresponding 3-(S)-derivative. Inhibitor 26exhibited potent activity against a panel of multidrug-resistant HIV-1 variants. A high resolution X-ray structure of 26-bound HIV-1 protease revealed important molecular insight into the ligand-binding site interactions. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis leading to cirrhosis remains a global health problem. The most common etiologies are alcoholism and viral infections. Liver fibrosis is associated with major changes in both quantity and composition of extracellular matix and leads to disorganization of the liver architecture and irreversible damage to the liver function. As of now there is no effective therapy to control fibrosis. The end product of fibrosis is abnormal synthesis and accumulation of type I collagen in the extracellular matrix, which is produced by activated stellate or Ito cells in the damaged liver. Therefore, inhibition of transcription of type I collagen should in principle inhibit its production and accumulation in liver. Normally, DNA exists in a duplex form. However, under some circumstances, DNA can assume triple helical (triplex) structures. Intermolecular triplexes, formed by the addition of a sequence-specific third strand to the major groove of the duplex DNA, have the potential to serve as selective gene regulators. Earlier, we demonstrated efficient triplex formation between the exogenously added triplex-forming oligodeoxyribonucleotides (TFOs) and a specific sequence in the promoter region of the COL1A1gene. In this study we used a rat model of liver fibrosis, induced by dimethylnitrosamine, to test whether these TFOs prevent liver fibrosis. Our results indicate that both the 25-mer and 18-mer TFOs, specific for the upstream nucleotide sequence from −141 to −165 (relative to the transcription start site) in the 5′ end of collagen gene promoter, effectively prevented accumulation of liver collagen and fibrosis. We also observed improvement in liver function tests. However, mutations in the TFO that eliminated formation of triplexes are ineffective in preventing fibrosis. We believe that these TFOs can be used as potential antifibrotic therapeutic molecules. [ABSTRACT FROM AUTHOR]

Coincident measurement of the Auger electron and fragment ion momenta emitted after carbon core-level photoionization of acetylene has yielded new understanding of how the dication fragments. Ab initio calculations and experimental data, including body-frame Auger angular distributions, are used to identify the parent electronic states and together yield a comprehensive map of the dissociation pathways which include surface crossings and barriers to direct dissociation. The Auger angular distributions for certain breakup channels show evidence of core-hole localization. [ABSTRACT FROM AUTHOR]

The structure-based design, synthesis, and biological evaluationof a series of nonpeptidic macrocyclic HIV protease inhibitors aredescribed. The inhibitors are designed to effectively fill in thehydrophobic pocket in the S1′−S2′ subsites andretain all major hydrogen bonding interactions with the protein backbonesimilar to darunavir (1)or inhibitor 2.The ring size, the effect of methyl substitution, and unsaturationwithin the macrocyclic ring structure were assessed. In general, cyclicinhibitors were significantly more potent than their acyclic homologues,saturated rings were less active than their unsaturated analoguesand a preference for 10- and 13-membered macrocylic rings was revealed.The addition of methyl substituents resulted in a reduction of potency.Both inhibitors 14band 14cexhibited markedenzyme inhibitory and antiviral activity, and they exerted potentactivity against multidrug-resistant HIV-1 variants. Protein−ligandX-ray structures of inhibitors 2and 14cprovided critical molecular insights into the ligand-binding siteinteractions. [ABSTRACT FROM AUTHOR]

We report the design, synthesis, and biological evaluation of a series of novel HIV-1 protease inhibitors. The inhibitors incorporate stereochemically defined flexible cyclic ethers/polyethers as high affinity P2-ligands. Inhibitors containing small ring 1,3-dioxacycloalkanes have shown potent enzyme inhibitory and antiviral activity. Inhibitors 3dand 3hare the most active inhibitors. Inhibitor 3dmaintains excellent potency against a variety of multi-PI-resistant clinical strains. Our structure−activity studies indicate that the ring size, stereochemistry, and position of oxygens are important for the observed activity. Optically active synthesis of 1,3-dioxepan-5-ol along with the syntheses of various cyclic ether and polyether ligands have been described. A protein−ligand X-ray crystal structure of 3d-bound HIV-1 protease was determined. The structure revealed that the P2-ligand makes extensive interactions including hydrogen bonding with the protease backbone in the S2-site. In addition, the P2-ligand in 3dforms a unique water-mediated interaction with the NH of Gly-48. [ABSTRACT FROM AUTHOR]

The potent new antiviral inhibitor GRL-98065 (1) of HIV-1 protease (PR) has been studied with PR variants containing the single mutations D30N, I50V, V82A, and I84Vthat provide resistance to the major clinical inhibitors. Compound 1had inhibition constants of 17-fold, 8-fold, 3-fold, and 3-fold, respectively, for PRD30N, PRI50V, PRV82A, and PRI84Vrelative to wild type PR. The chemically related darunavir had similar relative inhibition, except for PRD30N, where inhibitor 1was approximately 3-fold less potent. The high resolution (1.11−1.60 Å) crystal structures of PR mutant complexes with inhibitor 1showed small changes relative to the wild type enzyme. PRD30Nand PRV82Ashowed compensating interactions with inhibitor 1relative to those of PR, while reduced hydrophobic contacts were observed with PRI50Vand PRI84V. Importantly, inhibitor 1complexes showed fewer changes relative to wild type enzyme than reported for darunavir complexes. Therefore, inhibitor 1is a valuable addition to the antiviral inhibitors with high potency against resistant strains of HIV. [ABSTRACT FROM AUTHOR]

Oxalate decarboxylase from Bacillus subtilisis composed of two cupin domains, each of which contains a Mn(II) ion coordinated by four identical conserved residues. The similarity between the two Mn(II) sites has precluded previous attempts to distinguish them spectroscopically and complicated efforts to understand the catalytic mechanism. A multifrequency cw-EPR approach has now enabled us to show that the two Mn ions can be distinguished on the basis of their differing fine structure parameters and to observe that acetate and formate bind to Mn(II) in only one of the two sites. The EPR evidence is consistent with the hypothesis that this Mn-binding site is located in the N-terminal domain, in agreement with predictions based on a recent X-ray structure of the enzyme. [ABSTRACT FROM AUTHOR]

We have identified interatomic Coulombic decay (ICD) processes in the ArKr dimer following Ar 2p Auger decay, using momentum-resolved electron-ion-ion coincidence spectroscopy and simultaneously determining the kinetic energy of the ICD electron and the KER between Ar2+ and Kr+. We find that the spin-conserved ICD processes in which Ar2+(3p[?]33d) 1P and 3P decay to Ar2+(3p[?]2)1D and 3P, respectively, ionizing the Kr atom, are significantly stronger than the spin-flip ICD processes in which Ar2+(3p[?]33d) 1P and 3P decay to Ar2+(3p[?]2)3P and 1D, respectively. [ABSTRACT FROM AUTHOR]