A Novel Mitochondria-Targeting Iron Chelator Neuroprotects Multimodally via HIF-1 Modulation Against a Mitochondrial Toxin in a Dopaminergic Cell Model of Parkinson's Disease.

Coumarins are plant-derived polyphenolic compounds belonging to the benzopyrones family, possessing wide-ranging pharmaceutical applications including cytoprotection, which may translate into therapeutic potential for multiple diseases, including Parkinson's disease (PD). Here we demonstrate the neuroprotective potential of a new polyhydroxyl coumarin, N-(1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl)-2-(7-hydroxy-2-oxo-2H-chromen-4-yl)acetamide (CT51), against the mitochondrial toxin 1-methyl-4-phenylpyridinium (MPP+). MPP+'s mechanism of toxicity relates to its ability to inhibit complex I of the mitochondrial electron transport chain (METC), leading to adenosine triphosphate (ATP) depletion, increased reactive oxygen species (ROS) production, and apoptotic cell death, hence mimicking PD-related neuropathology. Dopaminergic differentiated human neuroblastoma cells were briefly pretreated with CT51, followed by toxin exposure. CT51 significantly restored somatic cell viability and neurite processes; hence, the drug targets cell bodies and axons thereby preserving neural function and circuitry against PD-related damage. Moreover, MPP+ emulates the iron dyshomeostasis affecting dopaminergic neurons in PD-affected brains, whilst CT51 was previously revealed as an effective iron chelator that preferentially partitions to mitochondria. We extend these findings by characterising the drug's interactive effects at the METC level. CT51 did not improve mitochondrial coupling efficiency. However, voltammetric measurements and high-resolution respirometry analysis revealed that CT51 acts as an antioxidant agent. Also, the neuronal protection afforded by CT51 associated with downregulating MPP+-induced upregulated expression of hypoxia-inducible factor 1 alpha (HIF-1α), a protein which regulates iron homeostasis and protects against certain forms of oxidative stress after translocating to mitochondria. Our findings support the further development of CT51 as a dual functioning iron chelator and antioxidant antiparkinsonian agent.

Is Your Accent Right for the Job? A Meta-Analysis on Accent Bias in Hiring Decisions.

Standard-accented job candidates are perceived as more hireable than non-standard-accented candidates. Two broad perspectives have emerged as to what drives this effect: (a) that it is a pragmatic response to the perception that non-standard accents can impede job-relevant communication (processing fluency explanation) and/or (b) that non-standard accents signal "otherness" and candidates are devalued as a result (prejudice explanation). This meta-analytic integration of 139 effect sizes (N = 4,576) examined these two perspectives. Standard-accented candidates were considered more hireable than non-standard-accented candidates (d = 0.47)-a bias that was stronger for high communication jobs. Other findings, however, are difficult to explain from a processing fluency explanation: candidates' relative comprehensibility was not a significant moderator of hiring bias. Moreover, the degree of accent bias was associated with perceptions of the candidates' social status, and accent bias was particularly pronounced among female candidates and for candidates who spoke in foreign (as compared with regional) accents.

Mosquito antiviral defense mechanisms: a delicate balance between innate immunity and persistent viral infection.

Mosquito-borne diseases are associated with major global health burdens. Aedes spp. and Culex spp. are primarily responsible for the transmission of the most medically important mosquito-borne viruses, including dengue virus, West Nile virus and Zika virus. Despite the burden of these pathogens on human populations, the interactions between viruses and their mosquito hosts remain enigmatic. Viruses enter the midgut of a mosquito following the mosquito's ingestion of a viremic blood meal. During infection, virus recognition by the mosquito host triggers their antiviral defense mechanism. Of these host defenses, activation of the RNAi pathway is the main antiviral mechanism, leading to the degradation of viral RNA, thereby inhibiting viral replication and promoting viral clearance. However, whilst antiviral host defense mechanisms limit viral replication, the mosquito immune system is unable to effectively clear the virus. As such, these viruses can establish persistent infection with little or no fitness cost to the mosquito vector, ensuring life-long transmission to humans. Understanding of the mosquito innate immune response enables the discovery of novel antivectorial strategies to block human transmission. This review provides an updated and concise summary of recent studies on mosquito antiviral immune responses, which is a key determinant for successful virus transmission. In addition, we will also discuss the factors that may contribute to persistent infection in mosquito hosts. Finally, we will discuss current mosquito transmission-blocking strategies that utilize genetically modified mosquitoes and Wolbachia-infected mosquitoes for resistance to pathogens.

Interpreting mosquito feeding patterns in Australia through an ecological lens: an analysis of blood meal studies.

BACKGROUND: Mosquito-borne pathogens contribute significantly to the global burden of disease, infecting millions of people each year. Mosquito feeding is critical to the transmission dynamics of pathogens, and thus it is important to understanding and interpreting mosquito feeding patterns. In this paper we explore mosquito feeding patterns and their implications for disease ecology through a meta-analysis of published blood meal results collected across Australia from more than 12,000 blood meals from 22 species. To assess mosquito-vertebrate associations and identify mosquitoes on a spectrum of generalist or specialist feeders, we analysed blood meal data in two ways; first using a novel odds ratio analysis, and secondly by calculating Shannon's diversity scores. RESULTS: We find that each mosquito species had a unique feeding association with different vertebrates, suggesting species-specific feeding patterns. Broadly, mosquito species could be grouped broadly into those that were primarily ornithophilic and those that fed more often on livestock. Aggregated feeding patterns observed across Australia were not explained by intrinsic variables such as mosquito genetics or larval habitats. We discuss the implications for disease transmission by vector mosquito species classified as generalist-feeders (such as Aedes vigilax and Culex annulirostris), or specialists (such as Aedes aegypti) in light of potential influences on mosquito host choice. CONCLUSIONS: Overall, we find that whilst existing blood meal studies in Australia are useful for investigating mosquito feeding patterns, standardisation of blood meal study methodologies and analyses, including the incorporation of vertebrate surveys, would improve predictions of the impact of vector-host interactions on disease ecology. Our analysis can also be used as a framework to explore mosquito-vertebrate associations, in which host availability data is unavailable, in other global systems.

Leptospirosis: An important zoonosis acquired through work, play and travel

BACKGROUND: Leptospirosis is one of the most common zoonotic diseases worldwide. Infection occurs through contact with infected animals, or soil or water that has been contaminated by the urine of infected animals. Risk factors include occupational and recreational exposures, contact with floodwaters, and travel to areas with a high risk of leptospirosis, particularly tropical, developing countries. With climate change, flood-related outbreaks are becoming more common. OBJECTIVE: This article aims to improve awareness of leptospirosis, and provide an update for general practitioners on its epidemiology, risk factors, clinical presentation, laboratory diagnosis, management and prevention. DISCUSSION: Leptospirosis is sometimes misdiagnosed because clinical presentation can be non-specific and overlap with many other causes of acute febrile illnesses. In patients with risk factors for leptospirosis, a high index of clinical suspicion is important to ensure early diagnosis and treatment. Delays in treatment could increase the risk of severe complications, including pulmonary haemorrhage, acute renal failure and acute liver failure.

The non-human reservoirs of Ross River virus: a systematic review of the evidence.

Understanding the non-human reservoirs of zoonotic pathogens is critical for effective disease control, but identifying the relative contributions of the various reservoirs of multi-host pathogens is challenging. For Ross River virus (RRV), knowledge of the transmission dynamics, in particular the role of non-human species, is important. In Australia, RRV accounts for the highest number of human mosquito-borne virus infections. The long held dogma that marsupials are better reservoirs than placental mammals, which are better reservoirs than birds, deserves critical review. We present a review of 50 years of evidence on non-human reservoirs of RRV, which includes experimental infection studies, virus isolation studies and serosurveys. We find that whilst marsupials are competent reservoirs of RRV, there is potential for placental mammals and birds to contribute to transmission dynamics. However, the role of these animals as reservoirs of RRV remains unclear due to fragmented evidence and sampling bias. Future investigations of RRV reservoirs should focus on quantifying complex transmission dynamics across environments.

Farming and the geography of nutrient production for human use: a transdisciplinary analysis.

BACKGROUND: Information about the global structure of agriculture and nutrient production and its diversity is essential to improve present understanding of national food production patterns, agricultural livelihoods, and food chains, and their linkages to land use and their associated ecosystems services. Here we provide a plausible breakdown of global agricultural and nutrient production by farm size, and also study the associations between farm size, agricultural diversity, and nutrient production. This analysis is crucial to design interventions that might be appropriately targeted to promote healthy diets and ecosystems in the face of population growth, urbanisation, and climate change. METHODS: We used existing spatially-explicit global datasets to estimate the production levels of 41 major crops, seven livestock, and 14 aquaculture and fish products. From overall production estimates, we estimated the production of vitamin A, vitamin B12, folate, iron, zinc, calcium, calories, and protein. We also estimated the relative contribution of farms of different sizes to the production of different agricultural commodities and associated nutrients, as well as how the diversity of food production based on the number of different products grown per geographic pixel and distribution of products within this pixel (Shannon diversity index [H]) changes with different farm sizes. FINDINGS: Globally, small and medium farms (≤50 ha) produce 51-77% of nearly all commodities and nutrients examined here. However, important regional differences exist. Large farms (>50 ha) dominate production in North America, South America, and Australia and New Zealand. In these regions, large farms contribute between 75% and 100% of all cereal, livestock, and fruit production, and the pattern is similar for other commodity groups. By contrast, small farms (≤20 ha) produce more than 75% of most food commodities in sub-Saharan Africa, southeast Asia, south Asia, and China. In Europe, west Asia and north Africa, and central America, medium-size farms (20-50 ha) also contribute substantially to the production of most food commodities. Very small farms (≤2 ha) are important and have local significance in sub-Saharan Africa, southeast Asia, and south Asia, where they contribute to about 30% of most food commodities. The majority of vegetables (81%), roots and tubers (72%), pulses (67%), fruits (66%), fish and livestock products (60%), and cereals (56%) are produced in diverse landscapes (H>1·5). Similarly, the majority of global micronutrients (53-81%) and protein (57%) are also produced in more diverse agricultural landscapes (H>1·5). By contrast, the majority of sugar (73%) and oil crops (57%) are produced in less diverse ones (H≤1·5), which also account for the majority of global calorie production (56%). The diversity of agricultural and nutrient production diminishes as farm size increases. However, areas of the world with higher agricultural diversity produce more nutrients, irrespective of farm size. INTERPRETATION: Our results show that farm size and diversity of agricultural production vary substantially across regions and are key structural determinants of food and nutrient production that need to be considered in plans to meet social, economic, and environmental targets. At the global level, both small and large farms have key roles in food and nutrition security. Efforts to maintain production diversity as farm sizes increase seem to be necessary to maintain the production of diverse nutrients and viable, multifunctional, sustainable landscapes. FUNDING: Commonwealth Scientific and Industrial Research Organisation, Bill & Melinda Gates Foundation, CGIAR Research Programs on Climate Change, Agriculture and Food Security and on Agriculture for Nutrition and Health funded by the CGIAR Fund Council, Daniel and Nina Carasso Foundation, European Union, International Fund for Agricultural Development, Australian Research Council, National Science Foundation, Gordon and Betty Moore Foundation, and Joint Programming Initiative on Agriculture, Food Security and Climate Change-Belmont Forum.