Seasonal and interannual effects of hypoxia on fish habitat quality in central Lake Erie

1. Hypoxia occurs seasonally in many stratified coastal marine and freshwater ecosystems when bottom dissolved oxygen (DO) concentrations are depleted below 2–3 mg O2 L-1. 2. We evaluated the effects of hypoxia on fish habitat quality in the central basin of Lake Erie from 1987 to 2005, using bioenergetic growth rate potential (GRP) as a proxy for habitat quality. We compared the effect of hypoxia on habitat quality of (i) rainbow smelt, Osmerus mordax mordax Mitchill (young-of-year, YOY, and adult), a cold-water planktivore, (ii) emerald shiner, Notropis atherinoides Rafinesque (adult), a warm-water planktivore, (iii) yellow perch, Perca flavescens Mitchill (YOY and adult), a cool-water benthopelagic omnivore and (iv) round goby Neogobius melanostomus Pallas (adult) a eurythermal benthivore. Annual thermal and DO profiles were generated from 1D thermal and DO hydrodynamics models developed for Lake Erie’s central basin. 3. Hypoxia occurred annually, typically from mid-July to mid-October, which spatially and temporally overlaps with otherwise high benthic habitat quality. Hypoxia reduced the habitat quality across fish species and life stages, but the magnitude of the reduction varied both among and within species because of the differences in tolerance to low DO levels and warm-water temperatures. 4. Across years, trends in habitat quality mirrored trends in phosphorus concentration and water column oxygen demand in central Lake Erie. The per cent reduction in habitat quality owing to hypoxia was greatest for adult rainbow smelt and round goby (mean: -35%), followed by adult emerald shiner (mean: -12%), YOY rainbow smelt (mean: -10%) and YOY and adult yellow perch (mean: -8.5%). 5. Our results highlight the importance of differential spatiotemporally interactive effects of DO and temperature on relative fish habitat quality and quantity. These effects have the potential to influence the performance of individual fish species as well as population dynamics, trophic interactions and fish community structure

2,4-Diaminopyrimidines as Potent Inhibitors of Trypanosoma brucei and Identification of Molecular Targets by a Chemical Proteomics Approach

The protozoan parasite Trypanosoma brucei is the causative agent of human African trypanosomiasis (HAT) or sleeping sickness, a fatal disease affecting nearly half a million people in sub-Saharan Africa. Current treatments for HAT have very poor safety profiles and are difficult to administer. There is an urgent need for new, safe and effective treatments for sleeping sickness. This work describes the discovery of 2,4-diaminopyrimidines, exemplified by 4-[4-amino-5-(2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidine-1-carboxylic acid phenylamide or SCYX-5070, as potent inhibitors of T. brucei growth in vitro and also in animal models for HAT. To determine the parasite proteins responsible for interaction with SCYX-5070 and related compounds, affinity pull-downs were performed followed by sequence analysis and parasite genome database searching. The work revealed that mitogen-activated protein kinases (MAPKs) and cdc2-related kinases (CRKs) are the major proteins specifically bound to the immobilized compound, suggesting their potential participation in the pharmacological effects of 2,4-diaminopyrimidines against trypanosomatid protozoan parasites. These data strongly support the use of 2,4-diminipyrimidines as leads for the development of new drug candidates for the treatment of HAT

Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model

Plasmodium falciparum causes most of the one million annual deaths from malaria. Drug resistance is widespread and novel agents against new targets are needed to support combination-therapy approaches promoted by the World Health Organization. Plasmodium species are purine auxotrophs. Blocking purine nucleoside phosphorylase (PNP) kills cultured parasites by purine starvation. DADMe-Immucillin-G (BCX4945) is a transition state analogue of human and Plasmodium PNPs, binding with picomolar affinity. Here, we test BCX4945 in Aotus primates, an animal model for Plasmodium falciparum infections. Oral administration of BCX4945 for seven days results in parasite clearance and recrudescence in otherwise lethal infections of P. falciparum in Aotus monkeys. The molecular action of BCX4945 is demonstrated in crystal structures of human and P. falciparum PNPs. Metabolite analysis demonstrates that PNP blockade inhibits purine salvage and polyamine synthesis in the parasites. The efficacy, oral availability, chemical stability, unique mechanism of action and low toxicity of BCX4945 demonstrate potential for combination therapies with this novel antimalarial agent

Ecohealth Villages: A Framework for an Ecosystem Approach to Health in Human Settlements

As life emerged on Earth, it began to affect its environments. It still does. The complex interactions between living things and their environments mediate the character of both. Today, this is apparent in the global impacts humans have made on ecosystems, with resultant reciprocal impacts on human health. This paper is concerned with that reciprocity, which may be considered as a link between ecosystems and human populations. We will distinguish an ecosystem approach to human health—or ecohealth—from One Health and planetary health perspectives. We will also propose a conceptual framework that can be used to distinguish human settlements as Ecohealth Villages. Broadly defined, an Ecohealth Village is a settlement that recognizes the interactions between healthy ecosystems and the health of people who live, work, learn, and play in it. The key principles of an Ecohealth Villages are as follows: community ownership, ecological restoration, sustainability, social and gender equity, integrated perspectives, and traditional practices and knowledge. Together, they support a holistic, ecosystem approach to health in human settlements, as demonstrated in case studies from Mexico and Aotearoa New Zealand