Phylogenomics reveals the history of host use in mosquitoes.

Mosquitoes have profoundly affected human history and continue to threaten human health through the transmission of a diverse array of pathogens. The phylogeny of mosquitoes has remained poorly characterized due to difficulty in taxonomic sampling and limited availability of genomic data beyond the most important vector species. Here, we used phylogenomic analysis of 709 single copy ortholog groups from 256 mosquito species to produce a strongly supported phylogeny that resolves the position of the major disease vector species and the major mosquito lineages. Our analyses support an origin of mosquitoes in the early Triassic (217 MYA [highest posterior density region: 188-250 MYA]), considerably older than previous estimates. Moreover, we utilize an extensive database of host associations for mosquitoes to show that mosquitoes have shifted to feeding upon the blood of mammals numerous times, and that mosquito diversification and host-use patterns within major lineages appear to coincide in earth history both with major continental drift events and with the diversification of vertebrate classes.

How often are male mosquitoes attracted to humans?

Many mosquito species live close to humans where females feed on human blood. While male mosquitoes do not feed on blood, it has long been recognized that males of some species can be attracted to human hosts. To investigate the frequency of male mosquito attraction to humans, we conducted a literature review and human-baited field trials, as well as laboratory experiments involving males and females of three common Aedes species. Our literature review indicated that male attraction to humans is limited to a small number of species, including Ae. aegypti and Ae. albopictus. In our human-baited field collections, only 4 out of 13 species captured included males. In laboratory experiments, we found that male Ae. notoscriptus and Ae. vigilax showed no attraction to humans, while male Ae. aegypti exhibited persistent attraction for up to 30 min. Both male and female Ae. aegypti displayed similar preferences for different human subjects, suggesting that male Ae. aegypti respond to similar cues as females. Additionally, we found that mosquito repellents applied to human skin effectively repelled male mosquitoes. These findings shed light on mosquito behaviour and have implications for mosquito control programmes, particularly those involving the release or monitoring of the male mosquito population.

First Report of Bacterial Pineapple Heart Rot Caused by Dickeya zeae in Puerto Rico.

In Puerto Rico, the agricultural production of pineapple (Ananas comosus (L.) Merr.) comprises nearly 5,000 tons harvested annually from over 250 ha (USDA 2018). With an annual income of approximately $3 million USD, pineapple ranks fourth in importance among Puerto Rican crops (USDA 2018). Recently, the pineapple industry on the island underwent a change from growing a local cultivar known as "Cabezona" to cultivar MD2, introduced from Hawaii around 1996 (SEA 2015), because this cultivar produces fruit more than once during a single growing season. In August 2018 (when the rainy season normally starts in Puerto Rico), soft rot symptoms appeared at commercial fields in Manatí (WGS 84 Lat 18.42694, Lng -66.44779) and persisted through 2019. Symptoms observed in the field included foliar water-soaked lesions with gas-filled blisters, especially at the base of the leaf. Leaves exhibited brown discoloration and a fetid odor (rot) at the basal portion of the plant. Finally, leaves collapsed at the center of the pineapple crown, effectively killing the apex and preventing the fruit from developing. Disease incidence ranged from 25% to 40% depending on the weather and season; when there was more rain, there was higher disease incidence. Symptomatic leaves were collected in February 2019, disinfected with 70% ethanol, and rinsed with sterile distilled water. Tissue sections (5mm2) were placed in nutrient agar. Bacterial colony-forming units (CFU) were a translucent cream color, circular, with a flat convex surface and wavy edge. Biochemical analysis showed that bacteria were Gram-negative, oxidase positive, catalase positive, and facultatively anaerobic. Pathogenicity was tested on leaves of one-and-a-half-year-old pineapple seedlings in humid chambers. Bacteria were grown on sterile nutrient agar for 3 days at 25 ± 2°C. Inoculation assays (three replications) were performed using 1X108 CFU/ml of bacteria suspended in sterile water and applied with a cotton swab to leaves wounded with a needle. The inoculated tissue was incubated at 28°C and kept in a dark environment. Negative controls were inoculated with sterile water. Five days after inoculation, foliar water-soaked lesions were observed, followed by the formation of brown leaf tissue and gas-filled blisters, the same symptoms observed in the field. A partial DNA sequence of the 16S rRNA gene of the bacterial isolate and the re-isolated bacteria were amplified using primers 27F and 1492R (Lane et al. 1985) and sequenced. The isolate was determined to the genus Dickeya through a BLAST® search against sequences available in the database of the National Center for Biotechnology Information (NCBI). This partial 16S rRNA sequence of the bacterial isolate was deposited in GenBank® at NCBI (Accession no. MT672704). To determine the identity of the Dickeya species, we sequenced the genes dnaA, gyrB, dnaX, and recN (Marrero et al. 2013) for the bacterial isolate (GenBank accession nos. OM276852, OM276853, OM276854, and OM276855) and conducted a Multilocus Sequence Analysis including reference Dickeya sequences of Marrero et al., 2013. The Phylogenetic analysis (using WinClada) resolved the Puerto Rican isolate as belonging to a clade broadly ascribable to D. zeae, most closely related to strains isolated from earlier Hawaiian pineapple bacterial heart rot outbreaks. Dickeya zeae was responsible for bacterial heart rot of pineapple in Malaysia and was later reported as the causal agent for outbreaks in Costa Rica and Hawaii (Kaneshiro et al. 2008; Sueno et al. 2014; Ramachandran et al. 2015). D. zeae had not previously been reported as causing bacterial heart rot in pineapples in Puerto Rico and this study points to a close relationship with strains first detected in Hawaii and which should further be explored to determine the precise nature of this relationship. This information should facilitate the adoption of effective control measures for this disease on the island, promote more effective methods of preventing future introductions of pathogens, and encourage further investigations into the occurrence of D. zeae on the island.

Drug and Alcohol Use with Condomless Anal Sex among Men Who Have Sex with Men in Melbourne, Australia: A Retrospective Data Analysis from 2011 to 2017.

Rises in condomless anal sex among men who have sex with men (MSM) have been reported over the last decade but there is less certainty about the role that drugs, alcohol, play in this change. We examined the changes in drug and alcohol use among 22,255 MSM reporting condomless anal sex at Melbourne Sexual Health Centre in 2011-2017. There was a 7% annual increase in using drugs before and/or during condomless anal sex but a 3% annual reduction in condomless anal sex while drunk. MSM taking PrEP were more likely to report condomless anal sex with drug use (AOR: 1.21; 95%CI: 1.07-1.37) and alcohol use (AOR: 1.29; 95%CI: 1.14-1.46) compared with MSM not taking PrEP.

Detection of the Japanese encephalitis vector mosquito Culex tritaeniorhynchus in Australia using molecular diagnostics and morphology.

BACKGROUND: Culex (Culex) tritaeniorhynchus is an important vector of Japanese encephalitis virus (JEV) affecting feral pigs, native mammals and humans. The mosquito species is widely distributed throughout Southeast Asia, Africa and Europe, and thought to be absent in Australia. METHODS: In February and May, 2020 the Medical Entomology unit of the Northern Territory (NT) Top End Health Service collected Cx. tritaeniorhynchus female specimens (n = 19) from the Darwin and Katherine regions. Specimens were preliminarily identified morphologically as the Vishnui subgroup in subgenus Culex. Molecular identification was performed using cytochrome c oxidase subunit 1 (COI) barcoding, including sequence percentage identity using BLAST and tree-based identification using maximum likelihood analysis in the IQ-TREE software package. Once identified using COI, specimens were reanalysed for diagnostic morphological characters to inform a new taxonomic key to related species from the NT. RESULTS: Sequence percentage analysis of COI revealed that specimens from the NT shared 99.7% nucleotide identity to a haplotype of Cx. tritaeniorhynchus from Dili, Timor-Leste. The phylogenetic analysis showed that the NT specimens formed a monophyletic clade with other Cx. tritaeniorhynchus from Southeast Asia and the Middle East. We provide COI barcodes for most NT species from the Vishnui subgroup to aid future identifications, including the first genetic sequences for Culex (Culex) crinicauda and the undescribed species Culex (Culex) sp. No. 32 of Marks. Useful diagnostic morphological characters were identified and are presented in a taxonomic key to adult females to separate Cx. tritaeniorhynchus from other members of the Vishnui subgroup from the NT. CONCLUSIONS: We report the detection of Cx. tritaeniorhynchus in Australia from the Darwin and Katherine regions of the NT. The vector is likely to be already established in northern Australia, given the wide geographical spread throughout the Top End of the NT. The establishment of Cx. tritaeniorhynchus in Australia is a concern to health officials as the species is an important vector of JEV and is now the sixth species from the subgenus Culex capable of vectoring JEV in Australia. We suggest that the species must now be continuously monitored during routine mosquito surveillance programmes to determine its current geographical spread and prevent the potential transmission of exotic JEV throughout Australia.

Evaluation of self-calibrated non-linear phase-contrast correction in pediatric and congenital cardiovascular magnetic resonance imaging.

BACKGROUND: The need for background error correction in phase-contrast flow analysis has historically posed a challenge in cardiac magnetic resonance (MR) imaging. While previous studies have shown that phantom correction improves flow measurements, it impedes scanner workflow. OBJECTIVE: To evaluate the efficacy of self-calibrated non-linear phase-contrast correction on flows in pediatric and congenital cardiac MR compared to phantom correction as the standard. MATERIALS AND METHODS: We retrospectively identified children who had great-vessel phase-contrast and static phantom sequences acquired between January 2015 and June 2015. We applied a novel correction method to each phase-contrast sequence post hoc. Uncorrected, non-linear, and phantom-corrected flows were compared using intraclass correlation. We used paired t-tests to compare how closely non-linear and uncorrected flows approximated phantom-corrected flows. In children without intra- or extracardiac shunts or significant semilunar valvular regurgitation, we used paired t-tests to compare how closely the uncorrected pulmonary-to-systemic flow ratio (Qp:Qs) and non-linear Qp:Qs approximated phantom-corrected Qp:Qs. RESULTS: We included 211 diagnostic-quality phase-contrast sequences (93 aorta, 74 main pulmonary artery [MPA], 21 left pulmonary artery [LPA], 23 right pulmonary artery [RPA]) from 108 children (median age 15 years, interquartile range 11-18 years). Intraclass correlation showed strong agreement between non-linear and phantom-corrected flow measurements but also between uncorrected and phantom-corrected flow measurements. Non-linear flow measurements did not more closely approximate phantom-corrected measurements than did uncorrected measurements for any vessel. In 39 children without significant shunting or regurgitation, mean non-linear Qp:Qs (1.07; 95% confidence interval [CI] = 1.01, 1.13) was no closer than mean uncorrected Qp:Qs (1.06; 95% CI = 1.00, 1.13) to mean phantom-corrected Qp:Qs (1.02; 95% CI = 0.98, 1.06). CONCLUSION: Despite strong agreement between self-calibrated non-linear and phantom correction, cardiac flows and shunt calculations with non-linear correction were no closer to phantom-corrected measurements than those without background correction. However, phantom-corrected flows also demonstrated minimal differences from uncorrected flows. These findings suggest that in the current era, more accurate phase-contrast flow measurements might limit the need for background correction. Further investigation of the clinical impact and optimal methods of background correction in the pediatric and congenital cardiac population is needed.

Silent susceptibility-weighted angiography to detect hemorrhagic lesions in the brain: a clinical and phantom study.

PURPOSE: To compare the effectiveness of silent susceptibility-weighted angiography (sSWAN), a new imaging technique with lower acoustic noise, with conventional susceptibility-weighted angiography (cSWAN) in the detection of intracranial hemorrhagic lesions. METHODS: We measured the acoustic and background noise during sSWAN and cSWAN imaging and calculated the contrast-to-noise ratio (CNR) of the phantom consisting of eight chambers with different concentrations of superparamagnetic iron oxide. In the clinical study, we calculated the CNRs of hemorrhagic lesions in 15 patients and evaluated the images for conspicuity and artifact on each sequence and scored them on a 4-point scale. We also evaluated whether hypointense areas observed on sSWAN or cSWAN increased in size from those on T2*-weighted imaging (T2*-WI). RESULTS: Acoustic noise for sSWAN (57.9 ± 0.32 dB [background noise 51.3 dB]) was significantly less than that for cSWAN (89.0 ± 0.22 dB [background noise 50.9 dB]). The CNRs of phantoms for sSWAN were slightly but not significantly lower than those for cSWAN (P = 0.18). The CNRs of hemorrhagic lesions did not show significant differences between sSWAN and cSWAN (P = 0.17). There were no significant differences between sSWAN and cSWAN with respect to the scores for conspicuity, artifact, and change in size of hypointense areas from T2*-WI. CONCLUSION: sSWAN is equivalent to cSWAN with respect to the image quality for the detection of hemorrhagic lesions but has lower acoustic noise.

The functional neuroanatomy of emotion processing in frontotemporal dementias.

Impaired processing of emotional signals is a core feature of frontotemporal dementia syndromes, but the underlying neural mechanisms have proved challenging to characterize and measure. Progress in this field may depend on detecting functional changes in the working brain, and disentangling components of emotion processing that include sensory decoding, emotion categorization and emotional contagion. We addressed this using functional MRI of naturalistic, dynamic facial emotion processing with concurrent indices of autonomic arousal, in a cohort of patients representing all major frontotemporal dementia syndromes relative to healthy age-matched individuals. Seventeen patients with behavioural variant frontotemporal dementia [four female; mean (standard deviation) age 64.8 (6.8) years], 12 with semantic variant primary progressive aphasia [four female; 66.9 (7.0) years], nine with non-fluent variant primary progressive aphasia [five female; 67.4 (8.1) years] and 22 healthy controls [12 female; 68.6 (6.8) years] passively viewed videos of universal facial expressions during functional MRI acquisition, with simultaneous heart rate and pupillometric recordings; emotion identification accuracy was assessed in a post-scan behavioural task. Relative to healthy controls, patient groups showed significant impairments (analysis of variance models, all P < 0.05) of facial emotion identification (all syndromes) and cardiac (all syndromes) and pupillary (non-fluent variant only) reactivity. Group-level functional neuroanatomical changes were assessed using statistical parametric mapping, thresholded at P < 0.05 after correction for multiple comparisons over the whole brain or within pre-specified regions of interest. In response to viewing facial expressions, all participant groups showed comparable activation of primary visual cortex while patient groups showed differential hypo-activation of fusiform and posterior temporo-occipital junctional cortices. Bi-hemispheric, syndrome-specific activations predicting facial emotion identification performance were identified (behavioural variant, anterior insula and caudate; semantic variant, anterior temporal cortex; non-fluent variant, frontal operculum). The semantic and non-fluent variant groups additionally showed complex profiles of central parasympathetic and sympathetic autonomic involvement that overlapped signatures of emotional visual and categorization processing and extended (in the non-fluent group) to brainstem effector pathways. These findings open a window on the functional cerebral mechanisms underpinning complex socio-emotional phenotypes of frontotemporal dementia, with implications for novel physiological biomarker development.

Toward an ecoregion scale evaluation of eDNA metabarcoding primers: A case study for the freshwater fish biodiversity of the Murray-Darling Basin (Australia).

High-throughput sequencing of environmental DNA (i.e., eDNA metabarcoding) has become an increasingly popular method for monitoring aquatic biodiversity. At present, such analyses require target-specific primers to amplify DNA barcodes from co-occurring species, and this initial amplification can introduce biases. Understanding the performance of different primers is thus recommended prior to undertaking any metabarcoding initiative. While multiple software programs are available to evaluate metabarcoding primers, all programs have their own strengths and weaknesses. Therefore, a robust in silico workflow for the evaluation of metabarcoding primers will benefit from the use of multiple programs. Furthermore, geographic differences in species biodiversity are likely to influence the performance of metabarcoding primers and further complicate the evaluation process. Here, an in silico workflow is presented that can be used to evaluate the performance of metabarcoding primers on an ecoregion scale. This workflow was used to evaluate the performance of published and newly developed eDNA metabarcoding primers for the freshwater fish biodiversity of the Murray-Darling Basin (Australia). To validate the in silico workflow, a subset of the primers, including one newly designed primer pair, were used in metabarcoding analyses of an artificial DNA community and eDNA samples. The results show that the in silico workflow allows for a robust evaluation of metabarcoding primers and can reveal important trade-offs that need to be considered when selecting the most suitable primer. Additionally, a new primer pair was described and validated that allows for more robust taxonomic assignments and is less influenced by primer biases compared to commonly used fish metabarcoding primers.

Discovery of N-(4-{[5-Fluoro-7-(2-methoxyethoxy)quinazolin-4-yl]amino}phenyl)-2-[4-(propan-2-yl)-1 H-1,2,3-triazol-1-yl]acetamide (AZD3229), a Potent Pan-KIT Mutant Inhibitor for the Treatment of Gastrointestinal Stromal Tumors.

While the treatment of gastrointestinal stromal tumors (GISTs) has been revolutionized by the application of targeted tyrosine kinase inhibitors capable of inhibiting KIT-driven proliferation, diverse mutations to this kinase drive resistance to established therapies. Here we describe the identification of potent pan-KIT mutant kinase inhibitors that can be dosed without being limited by the tolerability issues seen with multitargeted agents. This effort focused on identification and optimization of an existing kinase scaffold through the use of structure-based design. Starting from a series of previously reported phenoxyquinazoline and quinoline based inhibitors of the tyrosine kinase PDGFRα, potency against a diverse panel of mutant KIT driven Ba/F3 cell lines was optimized, with a particular focus on reducing activity against a KDR driven cell model in order to limit the potential for hypertension commonly seen in second and third line GIST therapies. AZD3229 demonstrates potent single digit nM growth inhibition across a broad cell panel, with good margin to KDR-driven effects. Selectivity over KDR can be rationalized predominantly by the interaction of water molecules with the protein and ligand in the active site, and its kinome selectivity is similar to the best of the approved GIST agents. This compound demonstrates excellent cross-species pharmacokinetics, shows strong pharmacodynamic inhibition of target, and is active in several in vivo models of GIST.

Variable-Density Single-Shot Fast Spin-Echo MRI with Deep Learning Reconstruction by Using Variational Networks.

Purpose To develop a deep learning reconstruction approach to improve the reconstruction speed and quality of highly undersampled variable-density single-shot fast spin-echo imaging by using a variational network (VN), and to clinically evaluate the feasibility of this approach. Materials and Methods Imaging was performed with a 3.0-T imager with a coronal variable-density single-shot fast spin-echo sequence at 3.25 times acceleration in 157 patients referred for abdominal imaging (mean age, 11 years; range, 1-34 years; 72 males [mean age, 10 years; range, 1-26 years] and 85 females [mean age, 12 years; range, 1-34 years]) between March 2016 and April 2017. A VN was trained based on the parallel imaging and compressed sensing (PICS) reconstruction of 130 patients. The remaining 27 patients were used for evaluation. Image quality was evaluated in an independent blinded fashion by three radiologists in terms of overall image quality, perceived signal-to-noise ratio, image contrast, sharpness, and residual artifacts with scores ranging from 1 (nondiagnostic) to 5 (excellent). Wilcoxon tests were performed to test the hypothesis that there was no significant difference between VN and PICS. Results VN achieved improved perceived signal-to-noise ratio (P = .01) and improved sharpness (P < .001), with no difference in image contrast (P = .24) and residual artifacts (P = .07). In terms of overall image quality, VN performed better than did PICS (P = .02). Average reconstruction time ± standard deviation was 5.60 seconds ± 1.30 per section for PICS and 0.19 second ± 0.04 per section for VN. Conclusion Compared with the conventional parallel imaging and compressed sensing reconstruction (PICS), the variational network (VN) approach accelerates the reconstruction of variable-density single-shot fast spin-echo sequences and achieves improved overall image quality with higher perceived signal-to-noise ratio and sharpness. © RSNA, 2018 Online supplemental material is available for this article.

Cardiac responses to viewing facial emotion differentiate frontotemporal dementias.

OBJECTIVE: To establish proof-of-principle for the use of heart rate responses as objective measures of degraded emotional reactivity across the frontotemporal dementia spectrum, and to demonstrate specific relationships between cardiac autonomic responses and anatomical patterns of neurodegeneration. METHODS: Thirty-two patients representing all major frontotemporal dementia syndromes and 19 healthy older controls performed an emotion recognition task, viewing dynamic, naturalistic videos of facial emotions while ECG was recorded. Cardiac reactivity was indexed as the increase in interbeat interval at the onset of facial emotions. Gray matter associations of emotional reactivity were assessed using voxel-based morphometry of patients' brain MR images. RESULTS: Relative to healthy controls, all patient groups had impaired emotion identification, whereas cardiac reactivity was attenuated in those groups with predominant fronto-insular atrophy (behavioral variant frontotemporal dementia and nonfluent primary progressive aphasia), but preserved in syndromes focused on the anterior temporal lobes (right temporal variant frontotemporal dementia and semantic variant primary progressive aphasia). Impaired cardiac reactivity correlated with gray matter atrophy in a fronto-cingulo-insular network that overlapped correlates of cognitive emotion processing. INTERPRETATION: Autonomic indices of emotional reactivity dissociate from emotion categorization ability, stratifying frontotemporal dementia syndromes and showing promise as novel biomarkers. Attenuated cardiac responses to the emotions of others suggest a core pathophysiological mechanism for emotional blunting and degraded interpersonal reactivity in these diseases.

Does Size Matter? An Experimental Evaluation of the Relative Abundance and Decay Rates of Aquatic Environmental DNA.

Environmental DNA (eDNA) is increasingly used to monitor aquatic macrofauna. Typically, short mitochondrial DNA fragments are targeted because these should be relatively more abundant in the environment as longer fragments will break into smaller fragments over time. However, longer fragments may permit more flexible primer design and increase taxonomic resolution for eDNA metabarcoding analyses, and recent studies have shown that long mitochondrial eDNA fragments can be extracted from environmental water samples. Nuclear eDNA fragments have also been proposed as targets, but little is known about their persistence in the aquatic environment. Here we measure the abundance of mitochondrial eDNA fragments of different lengths and of short nuclear eDNA fragments, originating from captive fish in experimental tanks, and we test whether longer mitochondrial and short nuclear fragments decay faster than short mitochondrial fragments following fish removal. We show that when fish are present, shorter mitochondrial fragments are more abundant in water samples than both longer mitochondrial fragments and short nuclear eDNA fragments. However, the rate of decay following fish removal was similar for all fragment types, suggesting that the differences in abundance resulted from differences in the rates at which different fragment types were produced rather than differences in their decay rates.

Quantitation of Endogenous Metabolites in Mouse Tumors Using Mass-Spectrometry Imaging.

Described is a quantitative-mass-spectrometry-imaging (qMSI) methodology for the analysis of lactate and glutamate distributions in order to delineate heterogeneity among mouse tumor models used to support drug-discovery efficacy testing. We evaluate and report on preanalysis-stabilization methods aimed at improving the reproducibility and efficiency of quantitative assessments of endogenous molecules in tissues. Stability experiments demonstrate that optimum stabilization protocols consist of frozen-tissue embedding, post-tissue-sectioning desiccation, and storage at -80 °C of tissue sections sealed in vacuum-tight containers. Optimized stabilization protocols are used in combination with qMSI methodology for the absolute quantitation of lactate and glutamate in tumors, incorporating the use of two different stable-isotope-labeled versions of each analyte and spectral-clustering performed on each tissue section using k-means clustering to allow region-specific, pixel-by-pixel quantitation. Region-specific qMSI was used to screen different tumor models and identify a phenotype that has low lactate heterogeneity, which will enable accurate measurements of lactate modulation in future drug-discovery studies. We conclude that using optimized qMSI protocols, it is possible to quantify endogenous metabolites within tumors, and region-specific quantitation can provide valuable insight into tissue heterogeneity and the tumor microenvironment.

Lightweight, compact, and high-performance 3T MR system for imaging the brain and extremities.

PURPOSE: To build and evaluate a small-footprint, lightweight, high-performance 3T MRI scanner for advanced brain imaging with image quality that is equal to or better than conventional whole-body clinical 3T MRI scanners, while achieving substantial reductions in installation costs. METHODS: A conduction-cooled magnet was developed that uses less than 12 liters of liquid helium in a gas-charged sealed system, and standard NbTi wire, and weighs approximately 2000 kg. A 42-cm inner-diameter gradient coil with asymmetric transverse axes was developed to provide patient access for head and extremity exams, while minimizing magnet-gradient interactions that adversely affect image quality. The gradient coil was designed to achieve simultaneous operation of 80-mT/m peak gradient amplitude at a slew rate of 700 T/m/s on each gradient axis using readily available 1-MVA gradient drivers. RESULTS: In a comparison of anatomical imaging in 16 patients using T2 -weighted 3D fluid-attenuated inversion recovery (FLAIR) between the compact 3T and whole-body 3T, image quality was assessed as equivalent to or better across several metrics. The ability to fully use a high slew rate of 700 T/m/s simultaneously with 80-mT/m maximum gradient amplitude resulted in improvements in image quality across EPI, DWI, and anatomical imaging of the brain. CONCLUSIONS: The compact 3T MRI system has been in continuous operation at the Mayo Clinic since March 2016. To date, over 200 patient studies have been completed, including 96 comparison studies with a clinical 3T whole-body MRI. The increased gradient performance has reliably resulted in consistently improved image quality.

Genome-Wide Analysis of Starvation-Selected Drosophila melanogaster-A Genetic Model of Obesity.

Experimental evolution affords the opportunity to investigate adaptation to stressful environments. Studies combining experimental evolution with whole-genome resequencing have provided insight into the dynamics of adaptation and a new tool to uncover genes associated with polygenic traits. Here, we selected for starvation resistance in populations of Drosophila melanogaster for over 80 generations. In response, the starvation-selected lines developed an obese condition, storing nearly twice the level of total lipids than their unselected controls. Although these fats provide a ∼3-fold increase in starvation resistance, the imbalance in lipid homeostasis incurs evolutionary cost. Some of these tradeoffs resemble obesity-associated pathologies in mammals including metabolic depression, low activity levels, dilated cardiomyopathy, and disrupted sleeping patterns. To determine the genetic basis of these traits, we resequenced genomic DNA from the selected lines and their controls. We found 1,046,373 polymorphic sites, many of which diverged between selection treatments. In addition, we found a wide range of genetic heterogeneity between the replicates of the selected lines, suggesting multiple mechanisms of adaptation. Genome-wide heterozygosity was low in the selected populations, with many large blocks of SNPs nearing fixation. We found candidate loci under selection by using an algorithm to control for the effects of genetic drift. These loci were mapped to a set of 382 genes, which associated with many processes including nutrient response, catabolic metabolism, and lipid droplet function. The results of our study speak to the evolutionary origins of obesity and provide new targets to understand the polygenic nature of obesity in a unique model system.

Quantifying the relationship between inhibition of VEGF receptor 2, drug-induced blood pressure elevation and hypertension.

BACKGROUND AND PURPOSE: Several anti-angiogenic cancer drugs that inhibit VEGF receptor (VEGFR) signalling for efficacy are associated with a 15-60% incidence of hypertension. Tyrosine kinase inhibitors (TKIs) that have off-target activity at VEGFR-2 may also cause blood pressure elevation as an undesirable side effect. Therefore, the ability to translate VEGFR-2 off-target potency into blood pressure elevation would be useful in development of novel TKIs. Here, we have sought to quantify the relationship between VEGFR-2 inhibition and blood pressure elevation for a range of kinase inhibitors. EXPERIMENTAL APPROACH: Porcine aortic endothelial cells overexpressing VEGFR-2 (PAE) were used to determine IC50 for VEGFR-2 phosphorylation. These IC50 values were compared with published reports of exposure attained during clinical use and the corresponding incidence of all-grade hypertension. Unbound average plasma concentration (Cav,u ) was selected to be the most appropriate pharmacokinetic parameter. The pharmacokinetic-pharmacodynamic (PKPD) relationship for blood pressure elevation was investigated for selected kinase inhibitors, using data derived either from clinical papers or from rat telemetry experiments. KEY RESULTS: All-grade hypertension was predominantly observed when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 . Furthermore, based on the PKPD analysis, an exposure-dependent blood pressure elevation >1 mmHg was observed only when the Cav,u was >0.1-fold of the VEGFR-2 (PAE) IC50 . CONCLUSIONS AND IMPLICATIONS: Taken together, these data show that the risk of blood pressure elevation is proportional to the amount of VEGFR-2 inhibition, and a margin of >10-fold between VEGFR-2 IC50 and Cav,u appears to confer a minimal risk of hypertension.

Reduced acoustic noise in diffusion tensor imaging on a compact MRI system.

PURPOSE: To investigate the feasibility of substantially reducing acoustic noise while performing diffusion tensor imaging (DTI) on a compact 3T (C3T) MRI scanner equipped with a 42-cm inner-diameter asymmetric gradient. METHODS: A-weighted acoustic measurements were made using 10 mT/m-amplitude sinusoidal waveforms, corresponding to echo-planar imaging (EPI) echo spacing of 0.25 to 5.0 ms, on a conventional, whole-body 3T MRI and on the C3T. Acoustic measurements of DTI with trapezoidal EPI waveforms were then made at peak gradient performance on the C3T (80 mT/m amplitude, 700 T/m/s slew rate) and at derated performance (33 mT/m, 10 to 50 T/m/s) for acoustic noise reduction. DTI was acquired in two different phantoms and in seven human subjects, with and without gradient-derating corresponding to multi- and single-shot acquisitions, respectively. RESULTS: Sinusoidal waveforms on the C3T were quieter by 8.5 to 15.6 A-weighted decibels (dBA) on average as compared to the whole-body MRI. The derated multishot DTI acquisition noise level was only 8.7 dBA (at 13 T/m/s slew rate) above ambient, and was quieter than non-derated, single-shot DTI by 22.3 dBA; however, the scan time was almost quadrupled. Although derating resulted in negligible diffusivity differences in the phantoms, small biases in diffusivity measurements were observed in human subjects (apparent diffusion coefficient = +9.3 ± 8.8%, fractional anisotropy = +3.2 ± 11.2%, radial diffusivity = +9.4 ± 16.8%, parallel diffusivity = +10.3 ± 8.4%). CONCLUSION: The feasibility of achieving reduced acoustic noise levels with whole-brain DTI on the C3T MRI was demonstrated. Magn Reson Med 79:2902-2911, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Auditory conflict and congruence in frontotemporal dementia.

Impaired analysis of signal conflict and congruence may contribute to diverse socio-emotional symptoms in frontotemporal dementias, however the underlying mechanisms have not been defined. Here we addressed this issue in patients with behavioural variant frontotemporal dementia (bvFTD; n = 19) and semantic dementia (SD; n = 10) relative to healthy older individuals (n = 20). We created auditory scenes in which semantic and emotional congruity of constituent sounds were independently probed; associated tasks controlled for auditory perceptual similarity, scene parsing and semantic competence. Neuroanatomical correlates of auditory congruity processing were assessed using voxel-based morphometry. Relative to healthy controls, both the bvFTD and SD groups had impaired semantic and emotional congruity processing (after taking auditory control task performance into account) and reduced affective integration of sounds into scenes. Grey matter correlates of auditory semantic congruity processing were identified in distributed regions encompassing prefrontal, parieto-temporal and insular areas and correlates of auditory emotional congruity in partly overlapping temporal, insular and striatal regions. Our findings suggest that decoding of auditory signal relatedness may probe a generic cognitive mechanism and neural architecture underpinning frontotemporal dementia syndromes.

Model-based denoising in diffusion-weighted imaging using generalized spherical deconvolution.

PURPOSE: Diffusion MRI often suffers from low signal-to-noise ratio, especially for high b-values. This work proposes a model-based denoising technique to address this limitation. METHODS: A generalization of the multi-shell spherical deconvolution model using a Richardson-Lucy algorithm is applied to noisy data. The reconstructed coefficients are then used in the forward model to compute denoised diffusion-weighted images (DWIs). The proposed method operates in the diffusion space and thus is complementary to image-based denoising methods. RESULTS: We demonstrate improved image quality on the DWIs themselves, maps of neurite orientation dispersion and density imaging, and diffusional kurtosis imaging (DKI), as well as reduced spurious peaks in deterministic tractography. For DKI in particular, we observe up to 50% error reduction and demonstrate high image quality using just 30 DWIs. This corresponds to greater than fourfold reduction in scan time if compared to the widely used 140-DWI acquisitions. We also confirm consistent performance in pathological data sets, namely in white matter lesions of a multiple sclerosis patient. CONCLUSION: The proposed denoising technique termed generalized spherical deconvolution has the potential of significantly improving image quality in diffusion MRI. Magn Reson Med 78:2428-2438, 2017. © 2017 International Society for Magnetic Resonance in Medicine.