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The pesticide azamethiphos used by the salmon industry to treat sea lice, is applied as a bath and subsequently discharged into the sea. The effects of azamethiphos concentration (0, 15 and 100 μg L

Reef-associated predators are thought to influence the distribution of invertebrates of surrounding sediment habitats. In this study, we analyzed the predation pressure and the distributional patterns of macro- and meiofaunal assemblages in soft sediments surrounding two coral reef sites at Rapa Nui (Easter Island), in the central South Pacific. We tested the hypothesis that reef-associated predators negatively affect sediment-dwelling invertebrates, causing macro- and meiofauna to be less abundant and diverse in soft sediments near the reefs. As expected, predation intensity was greater nearer the reef than farther away, but macro- and meiofaunal assemblages did not differ significantly with distance from the reef. Taxon richness of macro- and meiofaunal assemblages were similar irrespective of distance from the reef. Only meiofauna showed significant variation in total abundance with distance from the reef, but this trend was not consistent between the two study sites. No gradient in sediment texture was observed with distance from the reef. Underwater video recordings at one study site also revealed that local hydrodynamics cause frequent disturbance and resuspension of the upper sediment layers. Our results suggest that soft-sediment assemblages are constantly reshuffled by oceanic waves, thereby blurring the potential effects of predation on invertebrate assemblages closer to the reef.

In recent decades, the alteration of coastal food webs (via aquaculture, fishing, and leisure activities), nutrient loading, and an expansion of monitoring programs have prompted an apparent worldwide rise in Harmful Algae Blooms (HABs). Over this time, a parallel increase in HABs has also been observed in the Chilean southern austral region (Patagonia fjords). HAB species like Alexandrium catenella—responsible for Paralytic Shellfish Poisoning (PSP)—are of great public concern due to their negative socioeconomic impacts and significant northward geographical range expansion. Many toxic dinoflagellate species (like A. catenella) produce benthic resting cysts, yet a holistic understanding of the physical-chemical and biological conditions influencing the distributions of cysts in this region is lacking. In this study, we measured a combination of hydrographic (temperature, salinity, and dissolved oxygen) and sediment physical-chemical properties (temperature, pH and redox potential), in addition to meiofaunal abundances –as sediment bioturbators and potential cyst predators– to determine the factors influencing dinoflagellate cyst distribution, with emphasis on A. catenella in and around a “hotspot” area of southern Chile. An analysis of similarities (ANOSIM) test revealed significant differences (p

Background Due to the importance of both prostaglandins (PGs) and leukotrienes (LTs) as pro-inflammatory mediators, and the potential for eicosanoid shunting in the presence of pathway target inhibitors, we have investigated an approach to inhibiting the formation of both PGs and LTs as part of a multi-targeted drug discovery effort. Methods We generated ligand-protein X-ray crystal structures of known inhibitors of microsomal prostaglandin E2 synthase-1 (mPGES-1) and the 5-Lipoxygenase Activating Protein (FLAP), with their respective proteins, to understand the overlapping pharmacophores. We subsequently used molecular modeling and structure-based drug design (SBDD) to identify hybrid structures intended to inhibit both targets. Results This work enabled the preparation of compounds 4 and 5, which showed potent in vitro inhibition of both targets. Significance Our findings enhance the structural understanding of mPGES-1 and FLAP's unique ligand binding pockets and should accelerate the discovery of additional dual inhibitors for these two important integral membrane protein drug targets.

One of the challenges for targeting B-Raf(V600E) with small molecule inhibitors had been achieving adequate selectivity over the wild-type protein B-Raf(WT), as inhibition of the latter has been associated with hyperplasia in normal tissues. Recent studies suggest that B-Raf inhibitors inducing the 'DFG-in/αC-helix-out' conformation (Type IIB) likely will exhibit improved selectivity for B-Raf(V600E). To explore this hypothesis, we transformed Type IIA inhibitor (1) into a series of Type IIB inhibitors (sulfonamides and sulfamides 4-6) and examined the SAR. Three selectivity indices were introduced to facilitate the analyses: the B-Raf(V600E)/B-Raf(WT) biochemical ((b)S), cellular ((c)S) selectivity, and the phospho-ERK activation ((p)A). Our data indicates that α-branched sulfonamides and sulfamides show higher selectivities than the linear derivatives. We rationalized this finding based on analysis of structural information from the literature and provided evidence for a monomeric B-Raf-inhibitor complex previously hypothesized to be responsible for the desired B-Raf(V600E) selectivity.

The three Pim kinases are a small family of serine/threonine kinases regulating several signaling pathways that are fundamental to tumorigenesis. As such, the Pim kinases are a very attractive target for pharmacological inhibition in cancer therapy. Herein, we describe our efforts toward the development of a potent, pan-Pim inhibitor. The synthesis and hit-to-lead SAR development from a 3-(pyrazin-2-yl)-1H-indazole derived hit 2 to the identification of a series of potent, pan-Pim inhibitors such as 13o are described.

PIM kinases are a family of Ser/Thr kinases that are implicated in tumorigenesis. The discovery of a new class of PIM inhibitors, 5-(1H-indol-5-yl)-1,3,4-thiadiazol-2-amines, is discussed with optimized compounds showing excellent potency against all three PIM isoforms.

Research shows that those with greater social capital enjoy better physical and mental health. The current study illuminates a paradox of social capital which may afflict those involved in traumatic events. Several years of survey data reveal a dynamic picture of the link between social capital and stress following Hurricane Katrina. Results reveal that initially after Katrina, those who were more socially embedded carried the greatest load with respect to helping the displaced population, thus experiencing more stress. But over time, the most socially-involved then snapped back from their stressful experiences more rapidly than isolates. This confirms that over the course of stressful events, social involvement first exposes people to more stress, but as time passes, provides them a significant buffer against negative psychosocial experiences.

We reveal how a N-scan SAR strategy (systematic substitution of each CH group with a N atom) was employed for quinolinone-based S1P(1) agonist 5 to modulate physicochemical properties and optimize in vitro and in vivo activity. The diaza-analog 17 displays improved potency (hS1P(1) RI; 17: EC(50)=0.020 μM, 120% efficacy; 5: EC(50)=0.070 μM, 110% efficacy) and selectivity (hS1P(3) Ca(2+) flux; 17: EC(50) >25 μM; 5: EC(50)=1.5 μM, 92% efficacy), as well as enhanced pharmacokinetics (17: CL=0.15 L/h/kg, V(dss)=5.1L/kg, T(1/2)=24h, %F=110; 5: CL=0.93L/h/kg, V(dss)=11L/kg, T(1/2)=15 h, %F=60) and pharmacodynamics (17: 1.0mg/kg po, 24h PLC POC=-67%; 5: 3mg/kg po, 24h PLC POC=-51%) in rat.

Structure-activity relationship (SAR) investigations of a novel class of triazolopyridazinone p38α mitogen activated protein kinase (MAPK) inhibitors are disclosed. From these studies, increased in vitro potency was observed for 2,6-disubstituted phenyl moieties and N-ethyl triazolopyridazinone cores due to key contacts with Leu108, Ala157 and Val38. Further investigation led to the identification of three compounds, 3g, 3j and 3m that are highly potent inhibitors of LPS-induced MAPKAP kinase 2 (MK2) phosphorylation in 50% human whole blood (hWB), and possess desirable in vivo pharmacokinetic and kinase selectivity profiles.

Through the analysis of X-ray crystallographic information and previous SAR studies, a novel series of protein kinase B (PKB/AKT) inhibitors was developed. The compounds showed nanomolar inhibition of AKT1 and were selective against cyclin-dependent kinase 2 (CDK2).

This study integrates the civic community framework from sociology into ecological research on mortality rates. The main hypothesis is that communities with high levels of civic engagement, a strong institutional infrastructure for civic participation, and a vibrant entrepreneurial economic climate should have lower rates of all-cause mortality. The analysis drew on data from the CDC WONDER system database for all counties in the US. The results from weighted least squares analysis of county level all-cause mortality rates age-adjusted to the 2000 population provide substantial support for the civic community perspective. Net of a range of important control variables, civically strong communities exhibit significantly lower rates of all-cause mortality.

A series of 2-aminothiadiazole of inhibitors of AKT1 is described. SAR relationships are discussed, along with selectivity for protein kinase A (PKA) and cyclin-dependent kinase 2 (CDK2). Moderate selectivity observed in several compounds for AKT1 versus PKA is rationalized by X-ray crystallographic analysis. Key compounds showed activity in cellular assays measuring phosphorylation of two AKT substrates, PRAS40 and FKHRL1. Compound 30 was advanced to a mouse liver PD assay, where it showed dose-dependent inhibition of AKT activity, as measured by the inhibition of phospho-PRAS40.

A screening campaign of a diverse collection of approximately 250,000 small molecule compounds was performed to identify inhibitors of proline-rich tyrosine kinase 2 (Pyk2) with potential osteogenic activity in osteoblast cells. Compounds were prioritized based on selectivity following a counter-screen against focal adhesion kinase (FAK), a closely related kinase. 4-Amino and 5-aryl substituted pyridinone series were identified that showed strong biochemical potency against Pyk2 and up to 3700-fold selectivity over FAK. Modeling analysis suggested that structural differences in the substrate binding cleft could explain the high selectivity of these chemical series against FAK. Representative compounds from each series showed inhibition of Pyk2 autophosphorylation in 293T cells (IC(50) approximately 0.11 microM), complete inhibition of endogenous Pyk2 in A7r5 cells and increased levels of osteogenic markers in MC3T3 osteoblast cells (EC(50)'s approximately 0.01 microM). These results revealed a new class of compounds with osteogenic-inducing activity in osteoblast cells and a starting point for the development of more potent and selective Pyk2 inhibitors.

The effects of the disposal of copper mine tailings on the littoral meiofaunal assemblages of the Chañaral area of northern Chile were studied. Of the metals data collected, only in the case of copper was there a clear association with the tailings distribution in both the seawater and porewater samples, and it is assumed that the tailings on the beaches was the source of copper in the adjacent seawater. When compared to the reference sites, the meiofaunal assemblages at the impacted sites had significantly lower densities and taxa diversities; at the northern sites only the densities were lower. Otoplanid turbellarians were identified as characteristic of those beaches impacted by tailings. The combination of porewater copper and the amount of tailings present were identified as mostly responsible for the observed structure of the meiofaunal assemblages. It was also established that the variation in natural sediment grain size from beach to beach was not a significant factor in the observed differences in the meiofaunal assemblages. The two groups of meiofauna that proved to be most sensitive to the effects of tailings dumping were the foraminiferans and the harpacticoid copepods.

In order adequately to sample conformational space, methods for protein structure prediction make necessary simplifications that also prevent them from being as accurate as desired. Thus, the idea of feeding them, hierarchically, into a more accurate method that samples less effectively was introduced a decade ago but has not met with more than limited success in a few isolated instances. Ideally, the final stages should be able to identify the native state, show a good correlation with native similarity in order to add value to the selection process, and refine the structures even further. In this work, we explore the possibility of using state-of-the-art explicit solvent molecular dynamics and implicit solvent free energy calculations to accomplish all three of those objectives on 12 small, single-domain proteins, four each of alpha, beta and mixed topologies. We find that this approach is very successful in ranking the native and also enhances the structure selection of predictions generated from the Rosetta method.

Vectorization and performance of the generalized Born solvation model (GB) as it is implemented in the AMBER program is presented in this study. Nonbonded interactions computed within the generalized Born model use the pairwise approximation of Hawkins et al. [J. Phys. Chem. 100 (1996) 19,824], which is in turn a variant of the model proposed by Schaeffer and Froemmel [J. Mol. Biol. 216 (1990) 1045]. The performance of this implementation on CRAY SV1 vector machines is discussed with reference to several proteins. Loop vectorization has shown improvements by as much as a factor of 10. Comparison of the timings of the GB method against simulations using fully hydrated proteins favors the GB method.

The purpose of this study was to evaluate the use of a prosthetic anterior cruciate ligament (PACL) for the treatment of anterior cruciate ligament (ACL) deficient knees. Fifteen patients (mean age, 40 years; range, 27 to 51 years) underwent ACL reconstruction using a PACL made from ultrahigh molecular weight polyethylene. Eleven patients had chronic ACL insufficiency (greater than 26 weeks), whereas four patients had previous unsuccessful reconstructions. A 4.6-mm PACL was implanted intra-articularly through tibial and femoral bone tunnels and attached by screw fixation. All subjects underwent a standardized rehabilitation protocol. Patients returned for follow up at 3-, 6-, 9-, 12-, 18-, 24-, and greater than 24-month intervals for evaluation (range, 9 to 48 months). The mean preoperative Lysholm score for the PACL group was 56 points, whereas the mean score at final follow up was 86 points. For the pain and instability components of the Lysholm scoring scale the mean preoperative and postoperative scores were 13 and 23 points, respectively. On KT-1000 arthrometer testing, patients had a mean preoperative score of 9 mm maximum manual displacement. This was compared with a mean score of 3 mm at final follow up. There were four complications requiring operative intervention, for an overall rate of 26.7%. There were three failures (20%) necessitating revision, two of which were associated with rupture of the device and one with chronic synovitis and sterile effusions. One patient had a painful bursitis over the tibial screw that was removed and replaced with a shorter screw.The PACL does provide stability for patients with ACL insufficiency; however, its use is associated with a relatively high complication rate. This procedure may have merit in select patients whose autogenous tissue is not available or when harvesting the tissue is undesirable, such as in older, less active individuals.