Successful malaria elimination strategies require interventions that target changing vector behaviours

BACKGROUND: The ultimate long-term goal of malaria eradication was recently placed back onto the global health agenda. When planning for this goal, it is important to remember why the original Global Malaria Eradication Programme (GMEP), conducted with DDT-based indoor residual spraying (IRS), did not achieve its goals. One of the technical reasons for the failure to eliminate malaria was over reliance on a single intervention and subsequently the mosquito vectors developed behavioural resistance so that they did not come into physical contact with the insecticide.Hypothesis and how to test it: Currently, there remains a monolithic reliance on indoor vector control. It is hypothesized that an outcome of long-term, widespread control is that vector populations will change over time, either in the form of physiological resistance, changes in the relative species composition or behavioural resistance. The potential for, and consequences of, behavioural resistance was explored by reviewing the literature regarding vector behaviour in the southwest Pacific. DISCUSSION: Here, two of the primary vectors that were highly endophagic, Anopheles punctulatus and Anopheles koliensis, virtually disappeared from large areas where DDT was sprayed. However, high levels of transmission have been maintained by Anopheles farauti, which altered its behaviour to blood-feed early in the evening and outdoors and, thereby, avoiding exposure to the insecticides used in IRS. This example indicates that the efficacy of programmes relying on indoor vector control (IRS and long-lasting, insecticide-treated nets [LLINs]) will be significantly reduced if the vectors change their behaviour to avoid entering houses. CONCLUSIONS: Behavioural resistance is less frequently seen compared with physiological resistance (where the mosquito contacts the insecticide but is not killed), but is potentially more challenging to control programmes because the intervention effectiveness cannot be restored by rotating the insecticide to one with a different mode of action. The scientific community needs to urgently develop systematic methods for monitoring behavioural resistance and then to work in collaboration with vector control programmes to implement monitoring in sentinel sites. In situations where behavioural resistance is detected, there will be a need to target other bionomic vulnerabilities that may exist in the larval stages, during mating, sugar feeding or another aspect of the life cycle of the vector to continue the drive towards elimination

Gene flow between island populations of the malaria mosquito, Anopheles hinesorum, may have contributed to the spread of divergent host preference phenotypes

Anopheles hinesorum is a mosquito species with variable host preference. Throughout New Guinea and northern Australia, An. hinesorum feeds on humans (it is opportunistically anthropophagic) while in the south-west Pacific's Solomon Archipelago, the species is abundant but has rarely been found biting humans (it is exclusively zoophagic in most populations). There are at least two divergent zoophagic (nonhuman biting) mitochondrial lineages of An. hinesorum in the Solomon Archipelago representing two independent dispersals. Since zoophagy is a derived (nonancestral) trait in this species, this leads to the question: has zoophagy evolved independently in these two populations? Or conversely: has nuclear gene flow or connectivity resulted in the transfer of zoophagy? Although we cannot conclusively answer this, we find close nuclear relationships between Solomon Archipelago populations indicating that recent nuclear gene flow has occurred between zoophagic populations from the divergent mitochondrial lineages. Recent work on isolated islands of the Western Province (Solomon Archipelago) has also revealed an anomalous, anthropophagic island population of An. hinesorum. We find a common shared mitochondrial haplotype between this Solomon Island population and another anthropophagic population from New Guinea. This finding suggests that there has been recent migration from New Guinea into the only known anthropophagic population from the Solomon Islands. Although currently localized to a few islands in the Western Province of the Solomon Archipelago, if anthropophagy presents a selective advantage, we may see An. hinesorum emerge as a new malaria vector in a region that is now working on malaria elimination

Smallest Anopheles farauti occur during the peak transmission season in the Solomon Islands

Background: Malaria transmission varies in intensity amongst Solomon Island villages where Anopheles farauti is the only vector. This variation in transmission intensity might be explained by density-dependent processes during An. farauti larval development, as density dependence can impact adult size with associated fitness costs and daily survivorship. Methods: Adult anophelines were sampled from six villages in Western and Central Provinces, Solomon Islands between March 2014 and February 2017. The size of females was estimated by measuring wing lengths, and then analysed for associations with biting densities and rainfall. Results: In the Solomon Islands, three anopheline species, An. farauti, Anopheles hinesorum and Anopheles lungae, differed in size. The primary malaria vector, An. farauti, varied significantly in size among villages. Greater rainfall was directly associated with higher densities of An. farauti biting rates, but inversely associated with body size with the smallest mean sized mosquitoes present during the peak transmission period. A measurable association between body size and survivorship was not found. Conclusions: Density dependent effects are likely impacting the size of adult An. farauti emerging from a range of larval habitats. The data suggest that rainfall increases An. farauti numbers and that these more abundant mosquitoes are significantly smaller in size, but without any reduced survivorship being associated with smaller size. The higher malaria transmission rate in a high malaria focus village appears to be determined more by vector numbers than size or survivorship of the vectors

Influence of environmental factors on the abundance of Anopheles farauti larvae in large brackish water streams in Northern Guadalcanal, Solomon Islands

Background: The main vector of malaria in Solomon Islands is Anopheles farauti, which has a mainly coastal distribution. In Northern Guadalcanal, Solomon Islands, high densities of An. farauti are supported by large brackish streams, which in the dry season are dammed by localized sand migration. The factors controlling the high larval productivity of these breeding sites have not been identified. Accordingly the influence of environmental factors on the presence and density of An. farauti larvae was assessed in three large naturally dammed streams. Methods. Larval sites were mapped and anopheline larvae were collected monthly for 12 months (July 2007 to June 2008) from three streams using standard dippers. Larval collections were made from 10 locations spaced at 50 m intervals along the edge of each stream starting from the coast. At each collection point, floating filamentous algae, aquatic emergent plants, sun exposure, and salinity were measured. These environmental parameters along with rainfall were correlated with larval presence and density. Results: The presence and abundance of An. farauti larvae varied between streams and was influenced by the month of collection, and distance from the ocean (p < 0.001). Larvae were more frequently present and more abundant within 50 m of the ocean during the dry season when the streams were dammed. The presence and density of larvae were positively associated with aquatic emergent plants (presence: p = 0.049; density: p = 0.001). Although filamentous algae did not influence the presence of larvae, this factor did significantly influence the density of larvae (p < 0.001). Rainfall for the month prior to sampling was negatively associated with both larval presence and abundance (p < 0.001), as high rainfall flushed larvae from the streams. Salinity significantly influenced both the presence (p = 0.002) and density (p = 0.014) of larvae, with larvae being most present and abundant in brackish water at < 10 seawater. Conclusion: This study has demonstrated that the presence and abundance An. farauti larvae are influenced by environmental factors within the large streams. Understanding these parameters will allow for targeted cost effective implementation of source reduction and larviciding to support the frontline malaria control measures i.e. indoor residual spraying (IRS) and distribution of long-lasting insecticidal nets (LLINs)

Changes in vector species composition and current vector biology and behaviour will favour malaria elimination in Santa Isabel Province, Solomon Islands

Background: In 2009, Santa Isabel Province in the Solomon Islands embarked on a malaria elimination programme. However, very little is known in the Province about the anopheline fauna, which species are vectors, their bionomics and how they may respond to intensified intervention measures. The purpose of this study was to provide baseline data on the malaria vectors and to ascertain the possibility of successfully eliminating malaria using the existing conventional vector control measures, such as indoor residual spraying (IRS) and long-lasting insecticidal nets (LLIN). Methods. Entomological surveys were undertaken during October 2009. To determine species composition and distribution larval surveys were conducted across on the whole island. For malaria transmission studies, adult anophelines were sampled using human landing catches from two villages - one coastal and one inland. Results: Five Anopheles species were found on Santa Isabel: Anopheles farauti, Anopheles hinesorum, Anopheles lungae, Anopheles solomonis, and Anopheles nataliae. Anopheles hinesorum was the most widespread species. Anopheles farauti was abundant, but found only on the coast. Anopheles punctulatus and Anopheles koliensis were not found. Anopheles farauti was the only species found biting in the coastal village, it was incriminated as a vector in this study; it fed early in the night but equally so indoors and outdoors, and had a low survival rate. Anopheles solomonis was the main species biting humans in the inland village, it was extremely exophagic, with low survival rates, and readily fed on pigs. Conclusion: The disappearance of the two major vectors, An. punctulatus and An. koliensis, from Santa Isabel and the predominance of An. hinesorum, a non-vector species may facilitate malaria elimination measures. Anopheles farauti was identified as the main coastal vector with An. solomonis as a possible inland vector. The behaviour of An. solomonis is novel as it has not been previously found biting humans in any numbers. Both species appear to be short-lived, a characteristic that will limit their transmission potential. The early night feeding behaviour and a degree of outdoor biting seen in An. farauti and particularly in An. solomonis will require that their response to IRS and LLIN be closely monitored. In coastal villages, where large, favourable breeding sites allow for high numbers of An. farauti may require the addition of larval control to achieve elimination

Differential Host Immune Responses after Infection with Wild-Type or Lab-Attenuated Rabies Viruses in Dogs.

METHODOLOGY/PRINCIPAL FINDINGS: The experimental infection of dogs with TriGAS induced high levels of VNA in the serum, whereas wt RABV infection did not. Dogs infected with TriGAS developed antibodies against the virus including its glycoprotein, whereas dogs infected with DRV-NG11 only developed rabies antibodies that are presumably specific for the nucleoprotein, (N) and not the glycoprotein (G). We show that infection with TriGAS induces early activation of B cells in the draining lymph nodes and persistent activation of DCs and B cells in the blood. On the other hand, infection with DRV-NG11 fails to induce the activation of DCs and B cells and further reduces CD4 T cell production. Further, we show that intrathecal (IT) immunization of TriGAS not only induced high levels of VNA in the serum but also in the CSF while intramuscular (IM) immunization of TriGAS induced VNA only in the serum. In addition, high levels of total protein and WBC were detected in the CSF of IT immunized dogs, indicating the transient enhancement of blood-brain barrier (BBB) permeability, which is relevant to the passage of immune effectors from periphery into the CNS. CONCLUSIONS/SIGNIFICANCE: IM infection of dogs with TriGAS induced the production of serum VNA whereas, IT immunization of TriGAS in dogs induces high levels of VNA in the periphery as well as in the CSF and transiently enhances BBB permeability. In contrast, infection with wt DRV-NG11 resulted in the production of RABV-reactive antibodies but VNA and antibodies specific for G were absent. As a consequence, all of the dogs infected with wt DRV-NG11 succumbed to rabies. Thus the failure to activate protective immunity is one of the important features of RABV pathogenesis in dogs

The Active Galactic Nuclei in the Hobby-Eberly Telescope Dark Energy Experiment Survey (HETDEX). III. A Red Quasar with Extremely High Equivalent Widths Showing Powerful Outflows

We report an active galactic nucleus (AGN) with an extremely high equivalent width (EW), EWLyα+N V,rest ≳921 Å, in the rest frame, at z ∼ 2.24 in the Hobby-Eberly Telescope Dark Energy Experiment Survey (HETDEX), as a representative case of the high-EW AGN population. The continuum level is a nondetection in the HETDEX spectrum; thus the measured EW is a lower limit. The source is detected with significant emission lines (>7σ) at Lyα + N v λ1241, C iv λ1549, and a moderate emission line (∼4σ) at He ii λ1640 within the wavelength coverage of HETDEX (3500-5500 Å). The r-band magnitude is 24.57 from the Hyper Suprime-Cam-HETDEX joint survey with a detection limit of r = 25.12 at 5σ. The Lyα emission line spans a clearly resolved region of ∼10″ (85 kpc) in diameter. The Lyα line profile is strongly double peaked. The spectral decomposed blue gas and red gas Lyα emission are separated by ∼1.″2 (10.1 kpc) with a line-of-sight velocity offset of ∼1100 km s−1. This source is probably an obscured AGN with powerful winds

Data sharing and ontology use among agricultural genetics, genomics, and breeding databases and resources of the AgBioData Consortium

Over the last several decades, there has been rapid growth in the number and scope of agricultural genetics, genomics and breeding (GGB) databases and resources. The AgBioData Consortium (https://www.agbiodata.org/) currently represents 44 databases and resources covering model or crop plant and animal GGB data, ontologies, pathways, genetic variation and breeding platforms (referred to as 'databases' throughout). One of the goals of the Consortium is to facilitate FAIR (Findable, Accessible, Interoperable, and Reusable) data management and the integration of datasets which requires data sharing, along with structured vocabularies and/or ontologies. Two AgBioData working groups, focused on Data Sharing and Ontologies, conducted a survey to assess the status and future needs of the members in those areas. A total of 33 researchers responded to the survey, representing 37 databases. Results suggest that data sharing practices by AgBioData databases are in a healthy state, but it is not clear whether this is true for all metadata and data types across all databases; and that ontology use has not substantially changed since a similar survey was conducted in 2017. We recommend 1) providing training for database personnel in specific data sharing techniques, as well as in ontology use; 2) further study on what metadata is shared, and how well it is shared among databases; 3) promoting an understanding of data sharing and ontologies in the stakeholder community; 4) improving data sharing and ontologies for specific phenotypic data types and formats; and 5) lowering specific barriers to data sharing and ontology use, by identifying sustainability solutions, and the identification, promotion, or development of data standards. Combined, these improvements are likely to help AgBioData databases increase development efforts towards improved ontology use, and data sharing via programmatic means.Comment: 17 pages, 8 figure

Uncovering precision phenotype-biomarker associations in traumatic brain injury using topological data analysis

Background: Traumatic brain injury (TBI) is a complex disorder that is traditionally stratified based on clinical signs and symptoms. Recent imaging and molecular biomarker innovations provide unprecedented opportunities for improved TBI precision medicine, incorporating patho-anatomical and molecular mechanisms. Complete integration of these diverse data for TBI diagnosis and patient stratification remains an unmet challenge. Methods and findings: The Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) Pilot multicenter study enrolled 586 acute TBI patients and collected diverse common data elements (TBI-CDEs) across the study population, including imaging, genetics, and clinical outcomes. We then applied topology-based data-driven discovery to identify natural subgroups of patients, based on the TBI-CDEs collected. Our hypothesis was two-fold: 1) A machine learning tool known as topological data analysis (TDA) would reveal data-driven patterns in patient outcomes to identify candidate biomarkers of recovery, and 2) TDA-identified biomarkers would significantly predict patient outcome recovery after TBI using more traditional methods of univariate statistical tests. TDA algorithms organized and mapped the data of TBI patients in multidimensional space, identifying a subset of mild TBI patients with a specific multivariate phenotype associated with unfavorable outcome at 3 and 6 months after injury. Further analyses revealed that this patient subset had high rates of post-traumatic stress disorder (PTSD), and enrichment in several distinct genetic polymorphisms associated with cellular responses to stress and DNA damage (PARP1), and in striatal dopamine processing (ANKK1, COMT, DRD2). Conclusions: TDA identified a unique diagnostic subgroup of patients with unfavorable outcome after mild TBI that were significantly predicted by the presence of specific genetic polymorphisms. Machine learning methods such as TDA may provide a robust method for patient stratification and treatment planning targeting identified biomarkers in future clinical trials in TBI patients

Genome sequence of an Australian kangaroo, Macropus eugenii, provides insight into the evolution of mammalian reproduction and development.

BACKGROUND: We present the genome sequence of the tammar wallaby, Macropus eugenii, which is a member of the kangaroo family and the first representative of the iconic hopping mammals that symbolize Australia to be sequenced. The tammar has many unusual biological characteristics, including the longest period of embryonic diapause of any mammal, extremely synchronized seasonal breeding and prolonged and sophisticated lactation within a well-defined pouch. Like other marsupials, it gives birth to highly altricial young, and has a small number of very large chromosomes, making it a valuable model for genomics, reproduction and development. RESULTS: The genome has been sequenced to 2 × coverage using Sanger sequencing, enhanced with additional next generation sequencing and the integration of extensive physical and linkage maps to build the genome assembly. We also sequenced the tammar transcriptome across many tissues and developmental time points. Our analyses of these data shed light on mammalian reproduction, development and genome evolution: there is innovation in reproductive and lactational genes, rapid evolution of germ cell genes, and incomplete, locus-specific X inactivation. We also observe novel retrotransposons and a highly rearranged major histocompatibility complex, with many class I genes located outside the complex. Novel microRNAs in the tammar HOX clusters uncover new potential mammalian HOX regulatory elements. CONCLUSIONS: Analyses of these resources enhance our understanding of marsupial gene evolution, identify marsupial-specific conserved non-coding elements and critical genes across a range of biological systems, including reproduction, development and immunity, and provide new insight into marsupial and mammalian biology and genome evolution