Host behaviour and exposure risk in an insect-pathogen interaction

1. Studies of variability in host resistance to disease generally emphasize variability in susceptibility given exposure, neglecting the possibility that hosts may vary in behaviours that affect the risk of exposure. 2. In many insects, horizontal transmission of baculoviruses occurs when larvae consume foliage contaminated by the cadavers of virus-infected conspecific larvae; so, host behaviour may have a strong effect on the risk of infection. 3. We studied variability in the behaviour of gypsy moth (Lymantria dispar) larvae, which are able to detect and avoid virus-contaminated foliage. 4. Our results show that detection ability can be affected by the family line that larvae originate from, even at some distance froma virus-infected cadaver, and suggest that cadaver-detection ability may be heritable. 5. There is thus the potential for natural selection to act on cadaver-detection ability, and thereby to affect the dynamics of pathogen-driven cycles in gypsy moth populations. 6. We argue that host behaviour is a neglected component in studies of variability in disease resistance. © 2010 The Authors. Journal compilation © 2010 British Ecological Society

Nature-based solutions forming urban intervention approaches to anthropogenic climate change:a quantitative literature review

Discussion around anthropogenic climate change has occurred for over 100 years. However, in recent decades, these discussions have intensified due to increased confidence in scientific research highlighting adverse effects, increased knowledge breadth in climate science, and heightened public and political awareness and engagement on the topic. Climate change is now acknowledged as one of the biggest challenges and threats to modern lifestyles. Nature-based solutions (NBS), as a mediator and mitigator to adverse climate change effects, is an emerging area of expanding research collateral and practitioner literacy. To highlight current NBS knowledge, existing knowledge gaps, and research trends, a Quantitative Systematic Literature Review (QSLR) was undertaken (n = 54). This QSLR reveals the short temporal span of articles relating to NBS as a response to climate change, with most articles being of a research style format. NBS research focus areas were found to be dominated by ecological and infrastructure approaches to climate change mitigation, and ecological and technical positions were found to be most topical across the current climate change literature. Multiple knowledge gaps were identified by the review, namely the lack of broader conceptual approaches and knowledge acquisition regarding climate change responses via NBS, as well as the psychological relationship humans share with NBS and climate change, adverse or otherwise. These knowledge gaps highlight where future research inquiry may be directed to increase the value and completion of this research area. It is hoped that this QSLR will assist in increasing the profile of NBS in the multidisciplinary and complex response to anthropogenic climate change, as well as contribute to the growth in investment and implementation of NBS assets for a rigid and resilient global future

Improving the predictions of computational models of convection-enhanced drug delivery by accounting for diffusion non-gaussianity

Convection-enhanced delivery (CED) is an innovative method of drug delivery to the human brain, that bypasses the blood-brain barrier by injecting the drug directly into the brain. CED aims to target pathological tissue for central nervous system conditions such as Parkinson's and Huntington's disease, epilepsy, brain tumors, and ischemic stroke. Computational fluid dynamics models have been constructed to predict the drug distribution in CED, allowing clinicians advance planning of the procedure. These models require patient-specific information about the microstructure of the brain tissue, which can be collected non-invasively using magnetic resonance imaging (MRI) pre-infusion. Existing models employ the diffusion tensor, which represents Gaussian diffusion in brain tissue, to provide predictions for the drug concentration. However, those predictions are not always in agreement with experimental observations. In this work we present a novel computational fluid dynamics model for CED that does not use the diffusion tensor, but rather the diffusion probability that is experimentally measured through diffusion MRI, at an individual-participant level. Our model takes into account effects of the brain microstructure on the motion of drug molecules not taken into account in previous approaches, namely the restriction and hindrance that those molecules experience when moving in the brain tissue, and can improve the drug concentration predictions. The duration of the associated MRI protocol is 19 min, and therefore feasible for clinical populations. We first prove theoretically that the two models predict different drug distributions. Then, using in vivo high-resolution diffusion MRI data from a healthy participant, we derive and compare predictions using both models, in order to identify the impact of including the effects of restriction and hindrance. Including those effects results in different drug distributions, and the observed differences exhibit statistically significant correlations with measures of diffusion non-Gaussianity in brain tissue. The differences are more pronounced for infusion in white-matter areas of the brain. Using experimental results from the literature along with our simulation results, we show that the inclusion of the effects of diffusion non-Gaussianity in models of CED is necessary, if reliable predictions that can be used in the clinic are to be generated by CED models

Tract-specific differences in white matter microstructure between young adult APOE ε4 carriers and non-carriers:A replication and extension study

The parahippocampal cingulum bundle (PHCB) interconnects regions known to be vulnerable to early Alzheimer's disease (AD) pathology, including posteromedial cortex and medial temporal lobe. While AD-related pathology has been robustly associated with alterations in PHCB microstructure, specifically lower fractional anisotropy (FA) and higher mean diffusivity (MD), emerging evidence indicates that the reverse pattern is evident in younger adults at increased risk of AD. In one such study, Hodgetts et al. (2019) reported that healthy young adult carriers of the apolipoprotein-E (APOE) ε4 allele – the strongest common genetic risk factor for AD – showed higher FA and lower MD in the PHCB but not the inferior longitudinal fasciculus (ILF). These results are consistent with proposals claiming that heightened neural activity and intrinsic connectivity play a significant role in increasing posteromedial cortex vulnerability to amyloid-β and tau spread beyond the medial temporal lobe. Given the implications for understanding AD risk, here we sought to replicate Hodgetts et al.‘s finding in a larger sample (N = 128; 40 APOE ε4 carriers, 88 APOE ε4 non-carriers) of young adults (age range = 19–33). Extending this work, we also conducted an exploratory analysis using a more advanced measure of white matter microstructure: hindrance modulated orientational anisotropy (HMOA). Contrary to the original study, we did not observe higher FA or lower MD in the PHCB of APOE ε4 carriers relative to non-carriers. Bayes factors (BFs) further revealed moderate-to-strong evidence in support of these null findings. In addition, we observed no APOE ε4-related differences in PHCB HMOA. Our findings indicate that young adult APOE ε4 carriers and non-carriers do not differ in PHCB microstructure, casting some doubt on the notion that early-life variation in PHCB tract microstructure might enhance vulnerability to amyloid-β accumulation and/or tau spread

Impact of b-value on estimates of apparent fibre density

Recent advances in diffusion magnetic resonance imaging (dMRI) analysis techniques have improved our understanding of fibre-specific variations in white matter microstructure. Increasingly, studies are adopting multi-shell dMRI acquisitions to improve the robustness of dMRI-based inferences. However, the impact of b-value choice on the estimation of dMRI measures such as apparent fibre density (AFD) derived from spherical deconvolution is not known. Here, we investigate the impact of b-value sampling scheme on estimates of AFD. First, we performed simulations to assess the correspondence between AFD and simulated intra-axonal signal fraction across multiple b-value sampling schemes. We then studied the impact of sampling scheme on the relationship between AFD and age in a developmental population (n=78) aged 8-18 (mean=12.4, SD=2.9 years) using hierarchical clustering and whole brain fixel-based analyses. Multi-shell dMRI data were collected at 3.0T using ultra-strong gradients (300 mT/m), using 6 diffusion-weighted shells ranging from 0 – 6000 s/mm2. Simulations revealed that the correspondence between estimated AFD and simulated intra-axonal signal fraction was improved with high b-value shells due to increased suppression of the extra-axonal signal. These results were supported by in vivo data, as sensitivity to developmental age-relationships was improved with increasing b-value (b=6000 s/mm2, median R2 = .34; b=4000 s/mm2, median R2 = .29; b=2400 s/mm2, median R2 = .21; b=1200 s/mm2, median R2 = .17) in a tract-specific fashion. Overall, estimates of AFD and age-related microstructural development were better characterised at high diffusion-weightings due to improved correspondence with intra-axonal properties

Eddington-Limited Accretion in z~2 WISE-selected Hot, Dust-Obscured Galaxies

Hot, Dust-Obscured Galaxies, or "Hot DOGs", are a rare, dusty, hyperluminous galaxy population discovered by the WISE mission. Predominantly at redshifts 2-3, they include the most luminous known galaxies in the universe. Their high luminosities likely come from accretion onto highly obscured super massive black holes (SMBHs). We have conducted a pilot survey to measure the SMBH masses of five z~2 Hot DOGs via broad H_alpha emission lines, using Keck/MOSFIRE and Gemini/FLAMINGOS-2. We detect broad H_alpha emission in all five Hot DOGs. We find substantial corresponding SMBH masses for these Hot DOGs (~ 10^{9} M_sun), and their derived Eddington ratios are close to unity. These z~2 Hot DOGs are the most luminous AGNs at given BH masses, suggesting they are accreting at the maximum rates for their BHs. A similar property is found for known z~6 quasars. Our results are consistent with scenarios in which Hot DOGs represent a transitional, high-accretion phase between obscured and unobscured quasars. Hot DOGs may mark a special evolutionary stage before the red quasar and optical quasar phases, and they may be present at other cosmic epochs.Comment: 15 pages, 9 figures. Accepted by Ap

A comparative study of gradient nonlinearity correction strategies for processing diffusion data obtained with ultra-strong-gradient MRI scanner

Purpose: The analysis of diffusion data obtained under large gradient nonlinearities necessitates corrections during data reconstruction and analysis. While two such preprocessing pipelines have been proposed, no comparative studies assessing their performance exist. Furthermore, both pipelines neglect the impact of subject motion during acquisition, which, in the presence of gradient nonlinearities, induces spatio‐temporal B‐matrix variations. Here, spatio‐temporal B‐matrix tracking (STB) is proposed and its performance compared to established pipelines. Methods: Diffusion tensor MRI (DT‐MRI) was performed using a 300 mT/m gradient system. Data were acquired with volunteers positioned in regions with pronounced gradient nonlinearities, and used to compare the performance of six different processing pipelines, including STB. Results: Up to 30% errors were observed in DT‐MRI parameter estimates when neglecting gradient nonlinearities. Moreover, the order in which b0 inhomogeneity, eddy current and gradient nonlinearity corrections were performed was found to impact the consistency of parameter estimates significantly. Although, no pipeline emerged as a clear winner, the STB approach seemed to yield the most consistent parameter estimates under large gradient nonlinearities. Conclusions: Under large gradient nonlinearities, the choice of preprocessing pipeline significantly impacts the estimated diffusion parameters. Motion‐induced spatio‐temporal B‐matrix variations can lead to systematic bias in the parameter estimates, that can be ameliorated using the proposed STB framework

Drumming motor sequence training induces apparent myelin remodelling in Huntington’s disease: a longitudinal diffusion MRI and quantitative magnetization transfer study

Background:Impaired myelination may contribute to Huntington’s disease (HD) pathogenesis. Objective:This study assessed differences in white matter (WM) microstructure between HD patients and controls, and tested whether drumming training stimulates WM remodelling in HD. Furthermore, it examined whether training-induced microstructural changes are related to improvements in motor and cognitive function. Methods:Participants undertook two months of drumming exercises. Working memory and executive function were assessed before and post-training. Changes in WM microstructure were investigated with diffusion tensor magnetic resonance imaging (DT-MRI)-based metrics, the restricted diffusion signal fraction (Fr) from the composite hindered and restricted model of diffusion (CHARMED) and the macromolecular proton fraction (MPF) from quantitative magnetization transfer (qMT) imaging. WM pathways linking putamen and supplementary motor areas (SMA-Putamen), and three segments of the corpus callosum (CCI, CCII, CCIII) were studied using deterministic tractography. Baseline MPF differences between patients and controls were assessed with tract-based spatial statistics. Results:MPF was reduced in the mid-section of the CC in HD subjects at baseline, while a significantly greater change in MPF was detected in HD patients relative to controls in the CCII, CCIII, and the right SMA-putamen post-training. Further, although patients improved their drumming and executive function performance, such improvements did not correlate with microstructural changes. Increased MPF suggests training-induced myelin changes in HD. Conclusion:Though only preliminary and based on a small sample size, these results suggest that tailored behavioural stimulation may lead to neural benefits in early HD, that could be exploited for delaying disease progression

Tractography in the presence of multiple sclerosis lesions

Accurate anatomical localisation of specific white matter tracts and the quantification of their tract-specific microstructural damage in conditions such as multiple sclerosis (MS) can contribute to a better understanding of symptomatology, disease evolution and intervention effects. Diffusion MRI-based tractography is being used increasingly to segment white matter tracts as regions-of-interest for subsequent quantitative analysis. Since MS lesions can interrupt the tractography algorithm’s tract reconstruction, clinical studies frequently resort to atlas-based approaches, which are convenient but ignorant to individual variability in tract size and shape. Here, we revisit the problem of individual tractography in MS, comparing tractography algorithms using: (i) The diffusion tensor framework; (ii) constrained spherical deconvolution (CSD); and (iii) damped Richardson-Lucy (dRL) deconvolution. Firstly, using simulated and in vivo data from 29 MS patients and 19 healthy controls, we show that the three tracking algorithms respond differentially to MS pathology. While the tensor-based approach is unable to deal with crossing fibres, CSD produces spurious streamlines, in particular in tissue with high fibre loss and low diffusion anisotropy. With dRL, streamlines are increasingly interrupted in pathological tissue. Secondly, we demonstrate that despite the effects of lesions on the fibre orientation reconstruction algorithms, fibre tracking algorithms are still able to segment tracts that pass through areas with a high prevalence of lesions. Combining dRL-based tractography with an automated tract segmentation tool on data from 131 MS patients, the cortico-spinal tracts and arcuate fasciculi could be reconstructed in more than 90% of individuals. Comparing tract-specific microstructural parameters (fractional anisotropy, radial diffusivity and magnetisation transfer ratio) in individually segmented tracts to those from a tract probability map, we show that there is no systematic disease-related bias in the individually reconstructed tracts, suggesting that lesions and otherwise damaged parts are not systematically omitted during tractography. Thirdly, we demonstrate modest anatomical correspondence between the individual and tract probability-based approach, with a spatial overlap between 35 and 55%. Correlations between tract-averaged microstructural parameters in individually segmented tracts and the probability-map approach ranged between r=.53 ( p<.001 ) for radial diffusivity in the right cortico-spinal tract and r=.97 ( p<.001 ) for magnetisation transfer ratio in the arcuate fasciculi. Our results show that MS white matter lesions impact fibre orientation reconstructions but this does not appear to hinder the ability to anatomically reconstruct white matter tracts in MS. Individual tract segmentation in MS is feasible on a large scale and could prove a powerful tool for investigating diagnostic and prognostic markers

An engineered protein antagonist of K-Ras/B-Raf interaction

Ras is at the hub of signal transduction pathways controlling cell proliferation and survival. Its mutants, present in about 30% of human cancers, are major drivers of oncogenesis and render tumors unresponsive to standard therapies. Here we report the engineering of a protein scaffold for preferential binding to K-Ras G12D. This is the first reported inhibitor to achieve nanomolar affinity while exhibiting specificity for mutant over wild type (WT) K-Ras. Crystal structures of the protein R11.1.6 in complex with K-Ras WT and K-Ras G12D offer insight into the structural basis for specificity, highlighting differences in the switch I conformation as the major defining element in the higher affinity interaction. R11.1.6 directly blocks interaction with Raf and reduces signaling through the Raf/MEK/ERK pathway. Our results support greater consideration of the state of switch I and provide a novel tool to study Ras biology. Most importantly, this work makes an unprecedented contribution to Ras research in inhibitor development strategy by revealing details of a targetable binding surface. Unlike the polar interfaces found for Ras/effector interactions, the K-Ras/R11.1.6 complex reveals an extensive hydrophobic interface that can serve as a template to advance the development of high affinity, non-covalent inhibitors of K-Ras oncogenic mutants.National Institutes of Health (U.S.) (Grant 5-R01-CA096504-15