•The MT-DTI deep learning model was used to identify potent drugs for SARS-CoV-2.•Atazanavir, remdesivir, and Kaletra were predicted to inhibit SARS-CoV-2.•Rapamycin and tiotropium bromide may also ...be effective for SARS-CoV-2.
The infection of a novel coronavirus found in Wuhan of China (SARS-CoV-2) is rapidly spreading, and the incidence rate is increasing worldwide. Due to the lack of effective treatment options for SARS-CoV-2, various strategies are being tested in China, including drug repurposing. In this study, we used our pre-trained deep learning-based drug-target interaction model called Molecule Transformer-Drug Target Interaction (MT-DTI) to identify commercially available drugs that could act on viral proteins of SARS-CoV-2. The result showed that atazanavir, an antiretroviral medication used to treat and prevent the human immunodeficiency virus (HIV), is the best chemical compound, showing an inhibitory potency with Kd of 94.94 nM against the SARS-CoV-2 3C-like proteinase, followed by remdesivir (113.13 nM), efavirenz (199.17 nM), ritonavir (204.05 nM), and dolutegravir (336.91 nM). Interestingly, lopinavir, ritonavir, and darunavir are all designed to target viral proteinases. However, in our prediction, they may also bind to the replication complex components of SARS-CoV-2 with an inhibitory potency with Kd < 1000 nM. In addition, we also found that several antiviral agents, such as Kaletra (lopinavir/ritonavir), could be used for the treatment of SARS-CoV-2. Overall, we suggest that the list of antiviral drugs identified by the MT-DTI model should be considered, when establishing effective treatment strategies for SARS-CoV-2.
Diffusion tensor imaging (DTI), and fractional-anisotropy (FA) maps in particular, have shown promise in predicting areas of tumor recurrence in glioblastoma. However, analysis of peritumoral edema, ...where most recurrences occur, is impeded by free-water contamination. In this study, we evaluated the benefits of a novel, deep-learning-based approach for the free-water correction (FWC) of DTI data for prediction of later recurrence. We investigated 35 glioblastoma cases from our prospective glioma cohort. A preoperative MR image and the first MR scan showing tumor recurrence were semiautomatically segmented into areas of contrast-enhancing tumor, edema, or recurrence of the tumor. The 10th, 50th and 90th percentiles and mean of FA and mean-diffusivity (MD) values (both for the original and FWC-DTI data) were collected for areas with and without recurrence in the peritumoral edema. We found significant differences in the FWC-FA maps between areas of recurrence-free edema and areas with later tumor recurrence, where differences in noncorrected FA maps were less pronounced. Consequently, a generalized mixed-effect model had a significantly higher area under the curve when using FWC-FA maps (AUC = 0.9) compared to noncorrected maps (AUC = 0.77,
< 0.001). This may reflect tumor infiltration that is not visible in conventional imaging, and may therefore reveal important information for personalized treatment decisions.
Diffusion tensor imaging (DTI) is a well-established magnetic resonance imaging (MRI) technique used for studying microstructural changes in the white matter. As with many other imaging modalities, ...DTI images suffer from technical between-scanner variation that hinders comparisons of images across imaging sites, scanners and over time. Using fractional anisotropy (FA) and mean diffusivity (MD) maps of 205 healthy participants acquired on two different scanners, we show that the DTI measurements are highly site-specific, highlighting the need of correcting for site effects before performing downstream statistical analyses. We first show evidence that combining DTI data from multiple sites, without harmonization, may be counter-productive and negatively impacts the inference. Then, we propose and compare several harmonization approaches for DTI data, and show that ComBat, a popular batch-effect correction tool used in genomics, performs best at modeling and removing the unwanted inter-site variability in FA and MD maps. Using age as a biological phenotype of interest, we show that ComBat both preserves biological variability and removes the unwanted variation introduced by site. Finally, we assess the different harmonization methods in the presence of different levels of confounding between site and age, in addition to test robustness to small sample size studies.
•Significant site and scanner effects exist in DTI scalar maps.•Several multi-site harmonization methods are proposed.•ComBat performs the best at removing site effects in FA and MD.•Voxels associated with age in FA and MD are more replicable after ComBat.•ComBat is generalizable to other imaging modalities.
Purpose
White matter tractography reconstructions using conventional diffusion tensor imaging (DTI) near cerebrospinal fluid (CSF) spaces are often adversely affected by CSF partial volume effects ...(PVEs). This study evaluates the ability of free water elimination (FWE) DTI methods to minimize the PVE of CSF for deterministic tractography applications.
Materials and Methods
Ten healthy individuals were scanned with "traditional," FLAIR (fluid‐attenuated inversion recovery), and FWE DTI scans. The fornix, corpus callosum, and cingulum bundles were reconstructed using deterministic tractography. The FWE DTI scan was performed twice to separately match total acquisition time (long FWE) and number of measurements (encoding directions, short FWE) to the FLAIR and "traditional" DTI scans. PVE resolution was determined based on reconstructed tract volume. All reconstructions underwent blinded review for anatomical correctness, symmetry, and completeness.
Results
Reconstructions of the fornix demonstrated that the FWE and FLAIR scans produce more complete, anatomically plausible reconstructions than "traditional" DTI. Additionally, the tract reconstructions using FWE‐DTI were significantly larger than when FLAIR was used with DTI (P < 0.0005). FLAIR and the FWE methods led to signal‐to‐noise ratio (SNR) reductions of 33% and 11%, respectively, compared with conventional DTI. The long and short FWE acquisitions did not significantly (P ≥ 0.31) differ from one another for any of the reconstructed tracts.
Conclusion
The FWE diffusion model overcomes CSF PVE without the time, SNR, and volumetric coverage penalties inherent to FLAIR DTI. J. MAGN. RESON. IMAGING 2015;42:1572–1581.
To noninvasively evaluate the three-dimensional collagen fiber architecture of porcine meniscus using diffusion MRI, meniscal specimens were scanned using a 3D diffusion-weighted spin-echo pulse ...sequence at 7.0 T. The collagen fiber alignment was revealed in each voxel and the complex 3D collagen network was visualized for the entire meniscus using tractography. The proposed automatic segmentation methods divided the whole meniscus to different zones (Red-Red, Red-White, and White-White) and different parts (anterior, body, and posterior). The diffusion tensor imaging (DTI) metrics were quantified based on the segmentation results. The heatmap was generated to investigate the connections among different regions of meniscus. Strong zonal-dependent diffusion properties were demonstrated by DTI metrics. The fractional anisotropy (FA) value increased from 0.13 (White-White zone) to 0.26 (Red-Red zone) and the radial diffusivity (RD) value changed from 1.0 × 10
mm
/s (White-White zone) to 0.7 × 10
mm
/s (Red-Red zone). Coexistence of both radial and circumferential collagen fibers in the meniscus was evident by diffusion tractography. Weak connections were found between White-White zone and Red-Red zone in each part of the meniscus. The anterior part and posterior part were less connected, while the body part showed high connections to both anterior part and posterior part. The tractography based on diffusion MRI may provide a complementary method to study the integrity of meniscus and nondestructively visualize the 3D collagen fiber architecture.
•Diffusion MRI images were registered to Allen Mouse Brain Common Coordinate Framework for integration with Allen Developing Mouse Brain Atlas.•The differentials in the evolution of fiber orientation ...distributions were elucidated as significant contributors to the distinctive developmental patterns observed in white matter and gray matter.•Genes that govern structural and functional aspects of the brain exhibited correlations with metrics derived from diffusion tensor imaging and neurite orientation dispersion and density imaging, throughout the process of brain development.
Brain development is a highly complex process regulated by numerous genes at the molecular and cellular levels. Brain tissue exhibits serial microstructural changes during the development process. High-resolution diffusion magnetic resonance imaging (dMRI) affords a unique opportunity to probe these changes in the developing brain non-destructively. In this study, we acquired multi-shell dMRI datasets at 32 µm isotropic resolution to investigate the tissue microstructure alterations, which we believe to be the highest spatial resolution dMRI datasets obtained for postnatal mouse brains. We adapted the Allen Developing Mouse Brain Atlas (ADMBA) to integrate quantitative MRI metrics and spatial transcriptomics. Diffusion tensor imaging (DTI), diffusion kurtosis imaging (DKI), and neurite orientation dispersion and density imaging (NODDI) metrics were used to quantify brain development at different postnatal days. We demonstrated that the differential evolutions of fiber orientation distributions contribute to the distinct development patterns in white matter (WM) and gray matter (GM). Furthermore, the genes enriched in the nervous system that regulate brain structure and function were expressed in spatial correlation with age-matched dMRI. This study is the first one providing high-resolution dMRI, including DTI, DKI, and NODDI models, to trace mouse brain microstructural changes in WM and GM during postnatal development. This study also highlighted the genotype-phenotype correlation of spatial transcriptomics and dMRI, which may improve our understanding of brain microstructure changes at the molecular level.
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Summary
Objective
The epilepsy‐aphasia spectrum (EAS) is a heterogeneous group of age‐dependent childhood disorders characterized by sleep‐activated discharges associated with infrequent seizures and ...language, cognitive, and behavioral deficits. Defects in the GRIN2A gene, encoding a subunit of glutamate‐gated N‐methyl‐d‐aspartate (NMDA) receptors, represent the most important cause of EAS identified so far. Neocortical or thalamic lesions were detected in a subset of severe EAS disorders, and more subtle anomalies were reported in patients with so‐called “benign” phenotypes. However, whether brain structural alterations exist in the context of GRIN2A defects is unknown.
Methods
Magnetic resonance diffusion tensor imaging (MR‐DTI) was used to perform longitudinal analysis of the brain at 3 developmental timepoints in living mice genetically knocked out (KO) for Grin2a. In addition, electroencephalography (EEG) was recorded using multisite extracellular electrodes to characterize the neocortical activity in vivo.
Results
Microstructural alterations were detected in the neocortex, the corpus callosum, the hippocampus, and the thalamus of Grin2a KO mice. Most MR‐DTI alterations were detected at a specific developmental stage when mice were aged 30 days, but not at earlier (15 days) or later (2 months) ages. EEG analysis detected epileptiform discharges in Grin2a KO mice in the third postnatal week.
Significance
Grin2a KO mice replicated several anomalies found in patients with EAS disorders. Transient structural alterations detected by MR‐DTI recalled the age‐dependent course of EAS disorders, which in humans start during childhood and show variable outcome at the onset of adolescence. Together with the epileptiform discharges detected in young Grin2a KO mice, our data suggested the existence of early anomalies in the maturation of the neocortical and thalamocortical systems. Whereas the possible relationship of those anomalies with sleep warrants further investigations, our data suggest that Grin2a KO mice may serve as an animal model to study the neuronal mechanisms of EAS disorders and to design new therapeutic strategies.
Stroke or cerebrovascular accident (CVA) is a sudden occurrence, focal and non-convulsive neurologic deficit 1. In recent analysis (N=1541), spontaneous intracerebral haemorrhage (ICH), patients with ...intermediate Glasgow Coma Scale (GCS) between 9 to 12 may benefit from surgery, whereas those with higher or lower GCS may not 2.
According to WHO, every-year there were 10.3 million new cases and, overall high prevalence of 67% Ischemic strokes (IC) (Fig. 1) were observed in Middle East countries. Also, the incidence rate for females were high when compared to male 3.
The tissue plasminogen activator (tPA) is the only approved medication for IS, which must be administered within a three-hour space from the onset of symptoms for recovering results. Unfortunately, only 3- 5 percent reach the hospital in time, and the actual use of tPA is considerably low. This tPA also carries risk of increased intracranial hemorrhage so it is not used for haemorrhagic stroke 4. Management with surgery opted as least priority, because surgery benefits some and harms others 2.
The integration of stereotactic diffusion tensor imaging (DTI) tractography (Fig. 2) with Gamma Knife radiosurgery (GKRS) has increased therapeutic potential and safety 5. The procedure affects white matter tracts (predominantly the optic radiation and fasciculus - arcuate) are more vulnerable to radiation during stereotactic radiosurgery.
Integration of stereotactic tractography into Single-fraction stereotactic radiosurgery (SF-SRS) represents a promising tool for preventing the surgical complications in white matter tracts 6.
Amyloid-beta and tau are key molecules in the pathogenesis of Alzheimer’s disease, but it remains unclear how these proteins interact to promote disease. Here, by combining cross-sectional and ...longitudinal molecular imaging and network connectivity analyses in living humans, we identified two amyloid-beta/tau interactions associated with the onset and propagation of tau spreading. First, we show that the lateral entorhinal cortex, an early site of tau neurofibrillary tangle formation, is subject to remote, connectivity-mediated amyloid-beta/tau interactions linked to initial tau spreading. Second, we identify the inferior temporal gyrus as the region featuring the greatest local amyloid-beta/tau interactions and a connectivity profile well suited to accelerate tau propagation. Taken together, our data address long-standing questions regarding the topographical dissimilarity between early amyloid-beta and tau deposition.
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•Network flow-based model identifies tau propagation hubs in inferior temporal gyri•Remote Aβ-tau interactions in entorhinal cortex may trigger initial tau spreading•Local Aβ-tau interactions in inferior temporal gyrus may promote tau propagation•Connectivity-based model addresses the spatial incongruity between early Aβ and tau
Lee et al. show that the natural history of AD traverses a critical period that begins once Aβ emerges within entorhinal cortex (EC)-connected regions, continues as tau spreads from the EC into connected mesial temporal and limbic regions, and may end once Aβ and tau interact within the inferior temporal gyrus propagation hubs, whose connections are well suited to facilitate widespread neocortical tau propagation.
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