Gene-drive systems that enable super-Mendelian inheritance of a transgene have the potential to modify insect populations over a timeframe of a few years [AU please provide a real estimate, this seems vague]. We describe CRISPR-Cas9 endonuclease constructs that function as gene-drive systems in Anopheles gambiae, the main vector for malaria [AU:OK?]. We identified three genes (AGAP005958, AGAP011377 and AGAP007280) that confer a recessive female sterility phenotype upon disruption, and inserted into each locus CRISPR-Cas9 gene-drive constructs designed to target and edit each gene [AU:OK?]. For each locus targeted we observed strong gene drive at the molecular level, with transmission rates to progeny of 91 to 99.6%. Population modelling and cage experiments indicate that a CRISPR-Cas9 construct targeting one of these loci, AGAP007280, meets the minimum requirement for a gene drive targeting female reproduction in an insect population. These findings could expedite the development of gene drives to control suppress mosquito populations to levels that do not support malaria transmission.

Ciguatera Fish Poisoning (CFP) is the most frequently reported seafood-toxin illness in the world. It causes substantial human health, social, and economic impacts. The illness produces a complex array of gastrointestinal, neurological and neuropsychological, and cardiovascular symptoms, which may last days, weeks, or months. This paper is a general review of CFP including the human health effects of exposure to ciguatoxins (CTXs), diagnosis, human pathophysiology of CFP, treatment, detection of CTXs in fish, epidemiology of the illness, global dimensions, prevention, future directions, and recommendations for clinicians and patients. It updates and expands upon the previous review of CFP published by Friedman et al. (2008) and addresses new insights and relevant emerging global themes such as climate and environmental change, international market issues, and socioeconomic impacts of CFP. It also provides a proposed universal case definition for CFP designed to account for the variability in symptom presentation across different geographic regions. Information that is important but unchanged since the previous review has been reiterated. This article is intended for a broad audience, including resource and fishery managers, commercial and recreational fishers, public health officials, medical professionals, and other interested parties.

ex-chromosome drivers are genetic elements that interfere with chromosome segregation during meiosis and are over-represented in progeny 1. In heterogametic sex, they cause an unbalanced male-to-female ratio among offspring, which can potentially lead to population suppression or extinction. Relatively few sex-chromosome drives have been characterized, most likely because they produce an evolutionary conflict with the rest of the genome that selects for autosomal suppressors or resistant sex chromosomes 2,3. Mathematical modeling predicts that a driving sex distorter will spread in a population and, in the absence of resistance, cause eventual collapse 4,5. Population collapse using natural sex-chromosome drives has been reported in laboratory colonies of Drosophila 6,7. In the field, a population crash of the species Drosophila neotestacea was detected in Washington State due to a natural X-chromosome distorter that produced a female-only population 8. Therefore, sex-distorter drives could conceivably be harnessed for invasive pest or vector control 9,10. Although Y drives are less common than X drives, they have been described in Aedes aegypti and Culex pipiens mosquitoes 11,12. Y drives are particularly attractive for mosquito vector control because they can progressively reduce the number of females and hence disease transmission as they spread. In addition, Y drives are likely to be more effective than X drives because they can increase at a greater rate the fraction of heterogametic driving individuals 3-5. Synthetic sex distorters have been generated in A. gambiae mosquitoes by using site-specific nucleases such as I-PpoI or CRISPR-Cas9, which cleave conserved repeated sequences in the mosquito ribosomal DNA gene cluster located exclusively on the X chromosome 13,14. These nucleases, when expressed during spermatozoa development, selectively cleave the X chromosome, thereby favoring the production of Y-bearing gametes and causing a 95% male bias in the progeny 13,14. However, attempts to convert synthetic sex-ratio distorters into Y-chromosome drives have been unsuccessful so far. In most insect species, including A. gambiae, the sex chromosomes are transcriptionally shut down during gametogenesis, a process known as meiotic sex-chromosome inactivation 15,16 , which prevents the transcription of X-shredding nucleases if they are inserted into the Y chromosome (personal observation, A.C. and R.G.). Recently, a gene drive that targeted the dsx gene reached 100% frequency in 7-11 generations and crashed a caged population of 600 mosquitoes without inducing resistance 17. We hypothesized that it might be possible to circumvent meiotic sex-chromosome inactivation by developing an autosomal male-biased sex distorter and coupling sex-ratio distortion with drive. This could result in a quicker impact on disease transmission and a synergistic effect (robustness) between the sex distorter and gene-drive components. Here we report the design and validation of an SDGD to spread the X-chromosome-shredding I-PpoI endonu...

Homing-based gene drives use a germline source of nuclease to copy themselves at specific target sites in a genome and bias their inheritance. Such gene drives can be designed to spread and deliberately suppress populations of malaria mosquitoes by impairing female fertility. However, strong unintended fitness costs of the drive and a propensity to generate resistant mutations can limit a gene drive’s potential to spread. Alternative germline regulatory sequences in the drive element confer improved fecundity of carrier individuals and reduced propensity for target site resistance. This is explained by reduced rates of end-joining repair of DNA breaks from parentally deposited nuclease in the embryo, which can produce heritable mutations that reduce gene drive penetrance. We tracked the generation and selection of resistant mutations over the course of a gene drive invasion of a population. Improved gene drives show faster invasion dynamics, increased suppressive effect and later onset of target site resistance. Our results show that regulation of nuclease expression is as important as the choice of target site when developing a robust homing-based gene drive for population suppression.

OBJECTIVELittle is known about arsenic metabolism in diabetes development. We investigated the prospective associations of low-moderate arsenic exposure and arsenic metabolism with diabetes incidence in the Strong Heart Study.RESEARCH DESIGN AND METHODSA total of 1,694 diabetes-free participants aged 45–75 years were recruited in 1989–1991 and followed through 1998–1999. We used the proportions of urine inorganic arsenic (iAs), monomethylarsonate (MMA), and dimethylarsinate (DMA) over their sum (expressed as iAs%, MMA%, and DMA%) as the biomarkers of arsenic metabolism. Diabetes was defined as fasting glucose ≥126 mg/dL, 2-h glucose ≥200 mg/dL, self-reported diabetes history, or self-reported use of antidiabetic medications.RESULTSOver 11,263.2 person-years of follow-up, 396 participants developed diabetes. Using the leave-one-out approach to model the dynamics of arsenic metabolism, we found that lower MMA% was associated with higher diabetes incidence. The hazard ratios (95% CI) of diabetes incidence for a 5% increase in MMA% were 0.77 (0.63–0.93) and 0.82 (0.73–0.92) when iAs% and DMA%, respectively, were left out of the model. DMA% was associated with higher diabetes incidence only when MMA% decreased (left out of the model) but not when iAs% decreased. iAs% was also associated with higher diabetes incidence when MMA% decreased. The association between MMA% and diabetes incidence was similar by age, sex, study site, obesity, and urine iAs concentrations.CONCLUSIONSArsenic metabolism, particularly lower MMA%, was prospectively associated with increased incidence of diabetes. Research is needed to evaluate whether arsenic metabolism is related to diabetes incidence per se or through its close connections with one-carbon metabolism.