Effects of interactions between anthropogenic stressors and recurring perturbations on ecosystem resilience and collapse.

Insights into declines in ecosystem resilience and their causes and effects can inform preemptive action to avoid ecosystem collapse and loss of biodiversity, ecosystem services, and human well-being. Empirical studies of ecosystem collapse are rare and hampered by ecosystem complexity, nonlinear and lagged responses, and interactions across scales. We investigated how an anthropogenic stressor could diminish ecosystem resilience to a recurring perturbation by altering a critical ecosystem driver. We studied groundwater-dependent, peat-accumulating, fire-prone wetlands known as upland swamps in southeastern Australia. We hypothesized that underground mining (stressor) reduces resilience of these wetlands to landscape fires (perturbation) by diminishing groundwater, a key ecosystem driver. We monitored soil moisture as an indicator of ecosystem resilience during and after underground mining. After landscape fire, we compared responses of multiple state variables representing ecosystem structure, composition, and function in swamps within the mining footprint with unmined reference swamps. Soil moisture declined without recovery in swamps with mine subsidence (i.e., undermined), but was maintained in reference swamps over 8 years (effect size 1.8). Relative to burned reference swamps, burned undermined swamps showed greater loss of peat via substrate combustion; reduced cover, height, and biomass of regenerating vegetation; reduced postfire plant species richness and abundance; altered plant species composition; increased mortality rates of woody plants; reduced postfire seedling recruitment; and extirpation of a hydrophilic animal. Undermined swamps therefore showed strong symptoms of postfire ecosystem collapse, whereas reference swamps regenerated vigorously. We found that an anthropogenic stressor diminished the resilience of an ecosystem to recurring perturbations, predisposing it to collapse. Avoidance of ecosystem collapse hinges on early diagnosis of mechanisms and preventative risk reduction. It may be possible to delay or ameliorate symptoms of collapse or to restore resilience, but the latter appears unlikely in our study system due to fundamental alteration of a critical ecosystem driver. Efectos de las interacciones entre los estresantes antropogénicos y las perturbaciones recurrentes sobre la resiliencia y el colapso de los ecosistemas.

La comprensión de la declinación en la resiliencia de los ecosistemas y sus causas y efectos puede orientar las acciones preventivas para evitar el colapso ecosistémico y la pérdida de biodiversidad, servicios ambientales y bienestar humano. Los estudios empíricos del colapso ecosistémico son escasos y se enfrentan a obstáculos como la complejidad del ecosistema, respuestas rezagadas y no lineales e interacciones entre las escalas. Investigamos cómo un estresante antropogénico podría reducir la resiliencia del ecosistema a una perturbación recurrente mediante la alteración de un causante importante. Estudiamos los humedales dependientes de aguas subterráneas que acumulan turbas y son propicios a incendios conocidos como pantanos de tierras altas en el sureste de Australia. Nuestra hipótesis fue que la minería subterránea (estresante) reduce la resiliencia de estos humedales a incendios (perturbación) al disminuir el agua subterránea, un causante clave para el ecosistema. Monitoreamos la humedad del suelo como un indicador de la resiliencia del ecosistema durante y después de la minería subterránea. Después de los incendios, comparamos la respuesta de múltiples variables de estado que representaban la estructura, composición y función del ecosistema en los pantanos dentro de la huella minera con los pantanos referenciales sin minería. La humedad del suelo declinó sin recuperación en los pantanos con hundimientos mineros (es decir, socavones) pero se mantuvo en los pantanos referenciales durante ocho años (tamaño del efecto: 1.8). En relación a los pantanos referenciales incendiados, los pantanos con socavones e incendios mostraron una mayor pérdida de turba mediante la combustión del sustrato; reducción en la cobertura, altura y regeneración de biomasa de la vegetación; reducción en la riqueza y abundancia de especies vegetales post incendio; alteraciones en la composición de especies vegetales; incremento en la mortalidad de las plantas leñosas; reducción en el reclutamiento post incendio de plántulas; y la extirpación de un animal hidrofílico. Por lo tanto, los pantanos con socavones mostraron síntomas fuertes de un colapso ecosistémico post incendio, mientras que los pantanos referenciales se regeneraron vigorosamente. Descubrimos que los estresantes antropogénicos redujeron la resiliencia de un ecosistema a perturbaciones recurrentes, lo que lo predispone al colapso. La eliminación de este colapso depende de un diagnóstico temprano de mecanismos y reducción del riesgo preventivo. Puede ser posible retardar o mitigar los síntomas del colapso o restaurar la resiliencia, aunque lo último parece ser improbable en nuestro sistema de estudio debido a la alteración fundamental de un causante importante del ecosistema.

The Downstream Impacts of Hydropower Dams and Indigenous and Local Knowledge: Examples from the Peace-Athabasca, Mekong, and Amazon.

There has been much written about the negative social and environmental impacts of large hydropower dams, particularly the impacts on people and the environment caused by flooding linked to the creation of large reservoirs. There has also long been recognition of the importance of Indigenous and local knowledge for understanding ecological processes and environmental impacts. In this paper, however, we focus on a topic that has received insufficient consideration: the downstream impacts of dams, and the role of Indigenous and local knowledge in assessing and addressing these impacts. Using examples from three river basins in different parts of the world: the Peace-Athabasca in Canada, the Mekong in mainland Southeast Asia, and the Amazon in Brazil, we demonstrate that the downstream impacts of hydropower dams are often neglected due to the frequently long distances between dams and impacted areas, jurisdictional boundaries, and the less obvious nature of downstream impacts. We contend that Indigenous or local knowledge, if applied consistently and appropriately, has important roles to play in understanding and addressing these impacts, with the goal of avoiding, reducing, and appropriately compensating for the types of environmental injustices that are frequently associated with the downstream impacts of dams.

Fishers' multidimensional knowledge advances fisheries and aquatic science.

Fishers' Indigenous and local knowledge (ILK) has multidimensional contributions to improve fisheries and aquatic ecosystems science, ranging from algae to whales and including management, conservation, ecology, and impact assessment. The challenges are to sustain this knowledge, recognize its value, and to include ILK holders in resource management and decision-making.

Design of novel CXCR4 antagonists that are potent inhibitors of T-tropic (X4) HIV-1 replication.

A novel series of CXCR4 antagonists were identified based on the substantial redesign of AMD070. These compounds possessed potent anti-HIV-1 activity and showed excellent pharmacokinetics in rat and dog.

Design and synthesis of pyridin-2-yloxymethylpiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

A novel series of CCR5 antagonists were identified based on the redesign of Schering C. An SAR was established based on inhibition of CCR5 (RANTES) binding and these compounds exhibited potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells.

Design and synthesis of pyridin-2-ylmethylaminopiperidin-1-ylbutyl amide CCR5 antagonists that are potent inhibitors of M-tropic (R5) HIV-1 replication.

A series of CCR5 antagonists were optimized for potent inhibition of R5 HIV-1 replication in peripheral blood mononuclear cells. Compounds that met acceptable ADME criteria, selectivity, human plasma protein binding, potency shift in the presence of α-glycoprotein were evaluated in rat and dog pharmacokinetics.

Rhenium inhibitors of cathepsin B (ReO(SYS)X (where Y = S, py; X = Cl, Br, SPhOMe-p)): Synthesis and mechanism of inhibition.

The synthesis of four new oxorhenium(V) complexes containing the "3 + 1" mixed-ligand donor set, ReO(SYS)X (where Y = S, py; X = Cl, Br), is described. All of the complexes tested exhibited selectivity for cathepsin B over K. Most notably, compound 6, ReO(SSS-2,2')Br (IC50(cathepsin B) = 1.0 nM), was 260 times more potent against cathepsin B. It was also discovered that complexes containing the same tridentate (SSS) ligand were more potent when the leaving group was bromide versus chloride (e.g., IC50(cathepsin B): ReO(SSS-2,2')Cl (4), 8.8 nM; ReO(SSS-2,2')Br (6), 1.0 nM). Mechanistic studies with cathepsin B showed that both compounds 2 (ReO(SpyS)(SPhOMe-p)) and 4 were active-site-directed. Compound 2 was determined to be a tight-binding, reversible inhibitor, while compound 4 was a time-dependent, slowly reversible inhibitor. The results described in this paper show that the oxorhenium(V) "3 + 1" complexes are potent, selective inhibitors of cathepsin B and have potential for the treatment of cancer.

Efficacy and safety of azithromycin vs levofloxacin in the outpatient treatment of acute bacterial exacerbations of chronic bronchitis.

STUDY OBJECTIVES: To compare the safety and efficacy of oral azithromycin and levofloxacin in the treatment of outpatients with acute bacterial exacerbations of chronic bronchitis (ABECB). DESIGN: Randomized, double-blinded, double-dummy, multicenter trial with 1:1 treatment allocation. SETTING: Outpatient treatment setting. PATIENTS: Two hundred thirty-five male or female outpatients between the ages of 35 and 75 years who had received a clinical diagnosis of ABECB. INTERVENTIONS: Blinded treatment with either oral azithromycin, 500 mg on day 1 and 250 mg per day for days 2 to 5, or, oral levofloxacin, 500 mg q24h for 7 days. RESULTS: Both treatments were well-tolerated, with the majority of adverse events being GI in nature. Favorable clinical outcomes in clinically evaluable patients were demonstrated in 89% of patients receiving azithromycin and in 92% of patients receiving levofloxacin by day 4 of therapy. At day 24, the posttherapy visit, favorable responses were approximately 82% and 86%, respectively, for patients in the two treatment groups. The bacterial eradication rates of respiratory pathogens were 96% for azithromycin and 85% for levofloxacin. CONCLUSIONS: Despite increasing concerns over macrolide resistance and a higher incidence of Gram-negative pathogens, a standard 5-day course of oral azithromycin was clinically and bacteriologically equivalent to a 7-day course of oral levofloxacin in the treatment of patients with ABECB.

Design of substituted imidazolidinylpiperidinylbenzoic acids as chemokine receptor 5 antagonists: potent inhibitors of R5 HIV-1 replication.

The redesign of the previously reported thiophene-3-yl-methyl urea series, as a result of potential cardiotoxicity, was successfully accomplished, resulting in the identification of a novel potent series of CCR5 antagonists containing the imidazolidinylpiperidinyl scaffold. The main redesign criteria were to reduce the number of rotatable bonds and to maintain an acceptable lipophilicity to mitigate hERG inhibition. The structure-activity relationship (SAR) that was developed was used to identify compounds with the best pharmacological profile to inhibit HIV-1. As a result, five advanced compounds, 6d, 6e, 6i, 6h, and 6k, were further evaluated for receptor selectivity, antiviral activity against CCR5 using (R5) HIV-1 clinical isolates, and in vitro and in vivo safety. On the basis of these results, 6d and 6h were selected for further development.

Mitigating hERG Inhibition: Design of Orally Bioavailable CCR5 Antagonists as Potent Inhibitors of R5 HIV-1 Replication.

A series of CCR5 antagonists representing the thiophene-3-yl-methyl ureas were designed that met the pharmacological criteria for HIV-1 inhibition and mitigated a human ether-a-go-go related gene (hERG) inhibition liability. Reducing lipophilicity was the main design criteria used to identify compounds that did not inhibit the hERG channel, but subtle structural modifications were also important. Interestingly, within this series, compounds with low hERG inhibition prolonged the action potential duration (APD) in dog Purkinje fibers, suggesting a mixed effect on cardiac ion channels.

Metal compounds for the treatment of parasitic diseases.

The cysteine proteases of the trypanosomatid parasitic protozoa have been validated as targets for chemotherapy of Chagas' disease and leishmaniasis. Metal complexes of gold, platinum, iridium, palladium, rhodium and osmium have been reported to have activity against a variety of trypanosomatids, but the molecular target of these compounds has not been defined. The activity of gold(III) and palladium(II) cyclometallated complexes, and oxorhenium(V) complexes against mammalian and parasitic cysteine proteases was investigated. All gold(III) complexes (1-6) inhibited cathepsin B with IC(50) values in the range of 0.2-1.4 microM. Of the six palladium compounds, aceto[2,6-bis[(butylthio-kappa S)methyl]phenyl-kappa C]-, (SP-4-3)-palladium(II) (11) was the most potent inhibitor of cathepsin B with an IC(50) of 0.4 microM. A clear structure-activity relationship was observed with the oxorhenium(V) complexes with chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16) being the most potent inhibitor of cathepsin B with an IC(50) of 0.009 microM. Six complexes were further tested against the parasite cysteine proteases, cruzain from T. cruzi, and cpB from L. major; the most potent inhibitors were the two rhenium complexes (2(1H)-pyridinethionato-kappa S(2))[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (15) and chloro[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium(V) (16). The compounds were also evaluated in assays for parasite growth. Two oxorhenium(V) compounds ((p-methoxyphenylthiolato-S)[2,6-bis[(mercapto-kappa S)methyl]pyridine-kappa N(1)] oxorhenium(V) (14) and (methanethiolato)[2,2'-(thio-kappa S)bis[ethanethiolato-kappa S)]] oxorhenium (V) (18)) and the palladium compound 11 inhibited T. cruzi intracellular growth, and compound 11 inhibited promastigote growth in three Leishmania species. In conclusion this preliminary data indicates that metal complexes targeted at parasite cysteine proteases show promise for the treatment of both Chagas' disease and leishmaniasis.

Mekong River fish conservation zones in southern Laos: assessing effectiveness using local ecological knowledge.

Small-scale fisheries are important in Laos, where rural people heavily depend upon Mekong River and tributary fish stocks for their livelihoods. Increasing pressures from human exploitation and habitat disturbance, however, have raised serious concerns about the potential depletion of various species. This has led to the establishment of large numbers of Fish Conservation Zones (FCZs) or "no-take" fish sanctuaries in southern Laos based on a "community-based fisheries co-management" framework. This study uses the local ecological knowledge (LEK) of fishers to assess the effectiveness of village-managed FCZs in enhancing fish stocks in the mainstream Mekong River in Khong District, Champasak Province. Focus group interviews about species that are believed to have benefited from different FCZs are compared with parameters such as FCZ area, age, depth, localized gradient, water velocity, and the presence of wetland forests nearby. The results suggest that no one aspect is likely to account for variations in fish stocks; rather, it is the interaction between numerous factors that has the largest impact. Secondly, the results indicate that microhabitat diversity and protection are critical for maintaining and enhancing Mekong fisheries. Deep-water pools are particularly important as dry season refuges for many fish species, and FCZ depth may be the single most important environmental factor affecting the success of FCZs in the Mekong River. FCZs have the most potential to benefit relatively sedentary species, but may also benefit highly migratory species, given the right conditions. This study shows that integrated approaches to stock assessment that employ LEK and scientific fisheries management have considerable potential for improving Mekong capture-fisheries management.

Biodiversity conservation and resource tenure regimes: a case study from northeast Cambodia.

The management of tropical protected areas is a contentious issue in resource management and often leads to an unproductive polarization of viewpoints supporting either "protectionist" or "sustainable development" paradigms. This paper argues for a context-driven approach whereby effective management requires inputs from both paradigms in different situations. A key element of context is understanding long-practiced resource tenures and their ability to meet future conservation and livelihood goals. Different types of tenure arrangements are often required for different resources. This approach is illustrated by analysis of Virachey National Park in NE Cambodia. This park encompasses part of the ancestral territory of ethnic Brao people, who rely upon swidden agriculture, fish, terrestrial wildlife, and various nontimber forest products (NTFPs) for their livelihoods. These people have developed a mix of resource tenure regimes to promote sustainable use and to maximize local benefits. In the face of contemporary pressures, some of these traditional approaches are effective, while others are not. The paper suggests avenues for building on long-established management practices of the Brao to achieve park management goals while enhancing the welfare of the Brao people. A mix of private ownership, common property management, and central government involvement may be required to maximize benefits to local people and ensure long-term protection of biodiversity.

Enzymatic resolution of bicyclic 1-heteroarylamines using Candida antarctica lipase B.

Candida antarctica lipase B has been used to kinetically resolve a structurally diverse series of bicyclic 1-heteroaryl primary amines by enantioselective acetylation. High yields of either enantiomer could be obtained with excellent enantioselectivity (90-99% ee), while the undesired enantiomer could, in some cases, be recycled by thermal racemization. The absolute stereochemistry of the products was confirmed by an X-ray crystal structure.

Ruthenium(III) triazacyclononane dithiocarbamate, pyridinecarboxylate, or aminocarboxylate complexes as scavengers of nitric oxide.

The preparation of a series of [Ru(III)(tacn)(eta(2)-dtc)(eta(1)-dtc)][PF(6)] (tacn = 1,4,7-triazacyclononane; dtc = dimethyldithiocarbamate, diethyldithiocarbamate, pyrrolidinedithiocarbamate, l-prolinedithiocarbamate, l-prolinemethyl ester dithiocarbamate, l-N-methylisoleucinedithiocarbamate) complexes, 5-11, is described. Complex 5 reacts with NO to form the ruthenium nitrosyl complex 12. A series of [Ru(III)(tacn)(pyc)Cl][PF(6)] (pyc = 2-pyridinecarboxylic acid, 2,4- and 2,6-pyridinecarboxylic acid) complexes, 14-16, were prepared along with [Ru(III)(tacn)(mida)][PF(6)] (mida = N-methyliminodiacetic acid), 13, and [Ru(III)(Hnota)Cl], 17, (Hnota = 1-acetic acid-4,7-bismethylcarboxylate-1,4,7-triazacyclononane). Complexes 5-17 were evaluated for use as NO scavengers in an in vitro assay using RAW264 murine macrophage cells. [Ru(III)(tacn)(eta(2)-dtc)(eta(1)-dtc)][PF(6)] complexes 5-11 are very efficient NO scavengers in this assay.