Postzygotic Isolation Evolves before Prezygotic Isolation between Fresh and Saltwater Populations of the Rainwater Killifish, Lucania parva

Divergent natural selection has the potential to drive the evolution of reproductive isolation. The euryhaline killifish Lucania parva has stable populations in both fresh water and salt water. Lucania parva and its sister species, the freshwater L. goodei, are isolated by both prezygotic and postzygotic barriers. To further test whether adaptation to salinity has led to the evolution of these isolating barriers, we tested for incipient reproductive isolation within L. parva by crossing freshwater and saltwater populations. We found no evidence for prezygotic isolation, but reduced hybrid survival indicated that postzygotic isolation existed between L. parva populations. Therefore, postzygotic isolation evolved before prezygotic isolation in these ecologically divergent populations. Previous work on these species raised eggs with methylene blue, which acts as a fungicide. We found this fungicide distorts the pattern of postzygotic isolation by increasing fresh water survival in L. parva, masking species/population differences, and underestimating hybrid inviability

Paving the Way:Contributions of Big Data to Apicomplexan and Kinetoplastid Research

In the age of big data an important question is how to ensure we make the most out of the resources we generate. In this review, we discuss the major methods used in Apicomplexan and Kinetoplastid research to produce big datasets and advance our understanding of Plasmodium, Toxoplasma, Cryptosporidium, Trypanosoma and Leishmania biology. We debate the benefits and limitations of the current technologies, and propose future advancements that may be key to improving our use of these techniques. Finally, we consider the difficulties the field faces when trying to make the most of the abundance of data that has already been, and will continue to be, generated

Assessment of polygenic architecture and risk prediction based on common variants across fourteen cancers

Abstract: Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence

Phenotypic Screens Reveal Posaconazole as a Rapidly Acting Amebicidal Combination Partner for Treatment of Primary Amoebic Meningoencephalitis

Naegleria fowleri is the causative agent of primary amoebic meningoencephalitis (PAM), which is fatal in \u3e97% of cases. In this study, we aimed to identify new, rapidly acting drugs to increase survival rates. We conducted phenotypic screens of libraries of Food and Drug Administration–approved compounds and the Medicines for Malaria Venture Pathogen Box and validated 14 hits (defined as a 50% inhibitory concentration of \u3c1 μM). The hits were then prioritized by assessing the rate of action and efficacy in combination with current drugs used to treat PAM. Posaconazole was found to inhibit amoeba growth within the first 12 hours of exposure, which was faster than any currently used drug. In addition, posaconazole cured 33% of N. fowleri–infected mice at a dose of 20 mg/kg and, in combination with azithromycin, increased survival by an additional 20%. Fluconazole, which is currently used for PAM therapy, was ineffective in vitro and vivo. Our results suggest posaconazole could replace fluconazole in the treatment of PAM

Exploitation of Mangrove Endophytic Fungi for Infectious Disease Drug Discovery

There is an acute need for new and effective agents to treat infectious diseases. We conducted a screening program to assess the potential of mangrove-derived endophytic fungi as a source of new antibiotics. Fungi cultured in the presence and absence of small molecule epigenetic modulators were screened against Mycobacterium tuberculosis and the ESKAPE panel of bacterial pathogens, as well as two eukaryotic infective agents, Leishmania donovani and Naegleria fowleri. By comparison of bioactivity data among treatments and targets, trends became evident, such as the result that more than 60% of active extracts were revealed to be selective to a single target. Validating the technique of using small molecules to dysregulate secondary metabolite production pathways, nearly half (44%) of those fungi producing active extracts only did so following histone deacetylase inhibitory (HDACi) or DNA methyltransferase inhibitory (DNMTi) treatment