The majority of mosquito-borne illness is spread by a few mosquito species that have evolved to specialize in biting humans, yet the precise causes of this behavioral shift are poorly understood. We ...address this gap in the arboviral vector Aedes aegypti. We first collect and characterize the behavior of mosquitoes from 27 sites scattered across the species’ ancestral range in sub-Saharan Africa, revealing previously unrecognized variation in preference for human versus animal odor. We then use modeling to show that over 80% of this variation can be predicted by two ecological factors—dry season intensity and human population density. Finally, we integrate this information with whole-genome sequence data from 375 individual mosquitoes to identify a single underlying ancestry component linked to human preference. Genetic changes associated with human specialist ancestry were concentrated in a few chromosomal regions. Our findings suggest that human-biting in this important disease vector originally evolved as a by-product of breeding in human-stored water in areas where doing so provided the only means to survive the long, hot dry season. Our model also predicts that the rapid urbanization currently taking place in Africa will drive further mosquito evolution, causing a shift toward human-biting in many large cities by 2050.
•African populations of Ae. aegypti vary in preference for human versus animal odor•Preference for humans is associated with intense dry seasons and urbanization•Preference for humans has a single, shared genomic basis inside and outside Africa•Rapid urbanization could further increase human biting in many African cities by 2050
Rose et al. demonstrate that the evolution of human-biting in Aedes aegypti mosquitoes across Africa is associated with long, hot dry seasons and recent increases in human population density. This behavioral shift has a shared genomic basis inside and outside Africa; genetic changes were concentrated in key chromosomal regions.
Abstract
CRISPR systems have emerged as transformative tools for altering genomes in living cells with unprecedented ease, inspiring keen interest in increasing their specificity for perfectly ...matched targets. We have developed a novel approach for improving specificity by incorporating chemical modifications in guide RNAs (gRNAs) at specific sites in their DNA recognition sequence ('guide sequence') and systematically evaluating their on-target and off-target activities in biochemical DNA cleavage assays and cell-based assays. Our results show that a chemical modification (2′-O-methyl-3′-phosphonoacetate, or 'MP') incorporated at select sites in the ribose-phosphate backbone of gRNAs can dramatically reduce off-target cleavage activities while maintaining high on-target performance, as demonstrated in clinically relevant genes. These findings reveal a unique method for enhancing specificity by chemically modifying the guide sequence in gRNAs. Our approach introduces a versatile tool for augmenting the performance of CRISPR systems for research, industrial and therapeutic applications.
Post-translational phosphorylation is essential to human cellular processes, but the transient, heterogeneous nature of this modification complicates its study in native systems. We developed an ...approach to interrogate phosphorylation and its role in protein-protein interactions on a proteome-wide scale. We genetically encoded phosphoserine in recoded E. coli and generated a peptide-based heterologous representation of the human serine phosphoproteome. We designed a single-plasmid library encoding >100,000 human phosphopeptides and confirmed the site-specific incorporation of phosphoserine in >36,000 of these peptides. We then integrated our phosphopeptide library into an approach known as Hi-P to enable proteome-level screens for serine-phosphorylation-dependent human protein interactions. Using Hi-P, we found hundreds of known and potentially new phosphoserine-dependent interactors with 14-3-3 proteins and WW domains. These phosphosites retained important binding characteristics of the native human phosphoproteome, as determined by motif analysis and pull-downs using full-length phosphoproteins. This technology can be used to interrogate user-defined phosphoproteomes in any organism, tissue, or disease of interest.
Youth in high-poverty neighborhoods have high rates of emotional problems. Understanding neighborhood influences on mental health is crucial for designing neighborhood-level interventions.
To perform ...an exploratory analysis of associations between housing mobility interventions for children in high-poverty neighborhoods and subsequent mental disorders during adolescence.
The Moving to Opportunity Demonstration from 1994 to 1998 randomized 4604 volunteer public housing families with 3689 children in high-poverty neighborhoods into 1 of 2 housing mobility intervention groups (a low-poverty voucher group vs a traditional voucher group) or a control group. The low-poverty voucher group (n=1430) received vouchers to move to low-poverty neighborhoods with enhanced mobility counseling. The traditional voucher group (n=1081) received geographically unrestricted vouchers. Controls (n=1178) received no intervention. Follow-up evaluation was performed 10 to 15 years later (June 2008-April 2010) with participants aged 13 to 19 years (0-8 years at randomization). Response rates were 86.9% to 92.9%.
Presence of mental disorders from the Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) within the past 12 months, including major depressive disorder, panic disorder, posttraumatic stress disorder (PTSD), oppositional-defiant disorder, intermittent explosive disorder, and conduct disorder, as assessed post hoc with a validated diagnostic interview.
Of the 3689 adolescents randomized, 2872 were interviewed (1407 boys and 1465 girls). Compared with the control group, boys in the low-poverty voucher group had significantly increased rates of major depression (7.1% vs 3.5%; odds ratio (OR), 2.2 95% CI, 1.2-3.9), PTSD (6.2% vs 1.9%; OR, 3.4 95% CI, 1.6-7.4), and conduct disorder (6.4% vs 2.1%; OR, 3.1 95% CI, 1.7-5.8). Boys in the traditional voucher group had increased rates of PTSD compared with the control group (4.9% vs 1.9%, OR, 2.7 95% CI, 1.2-5.8). However, compared with the control group, girls in the traditional voucher group had decreased rates of major depression (6.5% vs 10.9%; OR, 0.6 95% CI, 0.3-0.9) and conduct disorder (0.3% vs 2.9%; OR, 0.1 95% CI, 0.0-0.4).
Interventions to encourage moving out of high-poverty neighborhoods were associated with increased rates of depression, PTSD, and conduct disorder among boys and reduced rates of depression and conduct disorder among girls. Better understanding of interactions among individual, family, and neighborhood risk factors is needed to guide future public housing policy changes.
The globally invasive mosquito subspecies
is an effective vector of human arboviruses, in part because it specializes in biting humans and breeding in human habitats. Recent work suggests that ...specialization first arose as an adaptation to long, hot dry seasons in the West African Sahel, where
relies on human-stored water for breeding. Here, we use whole-genome cross-coalescent analysis to date the emergence of human-specialist populationsand thus further probe the climate hypothesis. Importantly, we take advantage of the known migration of specialists out of Africa during the Atlantic Slave Trade to calibrate the coalescent clock and thus obtain a more precise estimate of the older evolutionary event than would otherwise be possible. We find that human-specialist mosquitoes diverged rapidly from ecological generalists approximately 5000 years ago, at the end of the African Humid Period-a time when the Sahara dried and water stored by humans became a uniquely stable, aquatic niche in the Sahel. We also use population genomic analyses to date a previously observed influx of human-specialist alleles into major West African cities. The characteristic length of tracts of human-specialist ancestry present on a generalist genetic background in Kumasi and Ouagadougou suggests the change in behavior occurred during rapid urbanization over the last 20-40 years. Taken together, we show that the timing and ecological context of two previously observed shifts towards human biting in
differ; climate was likely the original driver, but urbanization has become increasingly important in recent decades.
This paper describes the first version of a stand-alone runoff routing tool, mizuRoute. The mizuRoute tool post-processes runoff outputs from any distributed hydrologic model or land surface model to ...produce spatially distributed streamflow at various spatial scales from headwater basins to continental-wide river systems. The tool can utilize both traditional grid-based river network and vector-based river network data. Both types of river network include river segment lines and the associated drainage basin polygons, but the vector-based river network can represent finer-scale river lines than the grid-based network. Streamflow estimates at any desired location in the river network can be easily extracted from the output of mizuRoute. The routing process is simulated as two separate steps. First, hillslope routing is performed with a gamma-distribution-based unit-hydrograph to transport runoff from a hillslope to a catchment outlet. The second step is river channel routing, which is performed with one of two routing scheme options: (1) a kinematic wave tracking (KWT) routing procedure; and (2) an impulse response function – unit-hydrograph (IRF-UH) routing procedure. The mizuRoute tool also includes scripts (python, NetCDF operators) to pre-process spatial river network data. This paper demonstrates mizuRoute's capabilities to produce spatially distributed streamflow simulations based on river networks from the United States Geological Survey (USGS) Geospatial Fabric (GF) data set in which over 54 000 river segments and their contributing areas are mapped across the contiguous United States (CONUS). A brief analysis of model parameter sensitivity is also provided. The mizuRoute tool can assist model-based water resources assessments including studies of the impacts of climate change on streamflow.
An improved method for the chemical synthesis of RNA was developed utilizing a streamlined method for the preparation of phosphoramidite monomers and a single-step deprotection of the resulting ...oligoribonucleotide product using 1,2-diamines under anhydrous conditions. The process is compatible with most standard heterobase protection and employs a 2′-O-(1,1-dioxo-1λ6-thiomorpholine-4-carbothioate) as a unique 2′-hydroxyl protective group. Using this approach, it was demonstrated that the chemical synthesis of RNA can be as simple and robust as the chemical synthesis of DNA.
To prospectively evaluate the effect of preoperative functional magnetic resonance (MR) imaging localization of language and motor areas on therapeutic decision making in patients with potentially ...resectable brain tumors.
The Institutional Review Board approved this HIPAA-compliant study, and each patient gave written informed consent. Thirty-nine consecutive patients (19 male, 20 female; mean age, 42.2 years) referred for functional MR imaging for possible tumor resection were prospectively evaluated. A preoperative diagnosis of brain tumor was made in all patients. Sentence completion and bilateral hand squeeze tasks were used to map language and sensory motor areas. Neurosurgeons completed questionnaires regarding the proposed treatment plan before and after functional MR imaging and after surgery. They also gave confidence ratings for functional MR imaging results and estimated the effect on surgical time, extent of resection, and surgical approach. The effect of functional MR imaging on changes in treatment plan was assessed with the Wilcoxon signed rank test. Differences in confidence ratings between altered and unaltered treatment plans were assessed with the Mann-Whitney U test. The estimated influence of functional MR imaging on surgical time, extent of resection, and surgical approach was denoted with summary statistics.
Treatment plans before and after functional MR imaging differed in 19 patients (P < .05), with a more aggressive approach recommended after imaging in 18 patients. There were no significant differences in confidence ratings for functional MR imaging between altered and unaltered plans. Functional MR imaging resulted in reduced surgical time (estimated reduction, 15-60 minutes) in 22 patients who underwent surgery, a more aggressive resection in six, and a smaller craniotomy in two.
Functional MR imaging enables the selection of a more aggressive therapeutic approach than might otherwise be considered because of functional risk. In certain patients, surgical time may be shortened, the extent of resection increased, and craniotomy size decreased.
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