AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Audiohaptic feedback enhances motor performance in a low-fidelity simulated drilling task

When used in educational settings, simulations utilizing virtual reality (VR) technologies can reduce training costs while providing a safe and effective learning environment. Tasks can be easily modified to maximize learning objectives of different levels of trainees (e.g., novice, intermediate, expert), and can be repeated for the development of psychomotor skills. VR offers a multisensory experience, providing visual, auditory, and haptic sensations with varying levels of fidelity. While simulating visual and auditory stimuli is relatively easy and cost-effective, similar representations of haptic sensation still require further development. Evidence suggests that mixing high- and low-fidelity realistic sensations (e.g., audition and haptic) can improve the overall perception of realism, however, whether this also leads to improved performance has not been examined. The current study examined whether audiohaptic stimuli presented in a virtual drilling task can lead to improved motor performance and subjective realism, compared to auditory stimuli alone. Right-handed participants (n = 16) completed 100 drilling trials of each stimulus type. Performance measures indicated that participants overshot the target during auditory trials, and undershot the target during audiohaptic trials. Undershooting is thought to be indicative of improved performance, optimizing both time and energy requirements

Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells.

Radiation exposure is an occupational hazard for military personnel, some health care professionals, airport security screeners, and medical patients, with some individuals at risk for acute, high-dose exposures. Therefore, the biological effects of radiation, especially the potential for chromosome damage, are major occupational and health concerns. However, the biophysical mechanisms of chromosome instability subsequent to radiation-induced DNA damage are poorly understood. It is clear that interphase chromosomes occupy discrete structural and functional subnuclear domains, termed chromosome territories (CT), which may be organized into \u27neighborhoods\u27 comprising groups of specific CTs. We directly evaluated the relationship between chromosome positioning, neighborhood composition, and translocation partner choice in primary lymphocytes, using a cell-based system in which we could induce multiple, concentrated DNA breaks via high-dose irradiation. We critically evaluated mis-rejoining profiles and tested whether breaks occurring nearby were more likely to fuse than breaks occurring at a distance. We show that CT neighborhoods comprise heterologous chromosomes, within which inter-CT distances directly relate to translocation partner choice. These findings demonstrate that interphase chromosome arrangement is a principal factor in genomic instability outcomes in primary lymphocytes, providing a structural context for understanding the biological effects of radiation exposure, and the molecular etiology of tumor-specific translocation patterns

Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells.

International audienc

Chromosome neighborhood composition determines translocation outcomes after exposure to high-dose radiation in primary cells

Abstract Radiation exposure is an occupational hazard for military personnel, some health care professionals, airport security screeners, and medical patients, with some individuals at risk for acute, high-dose exposures. Therefore, the biological effects of radiation, especially the potential for chromosome damage, are major occupational and health concerns. However, the biophysical mechanisms of chromosome instability subsequent to radiationinduced DNA damage are poorly understood. It is clear that interphase chromosomes occupy discrete structural and functional subnuclear domains, termed chromosome territories (CT), which may be organized into Fneighborhoods_ comprising groups of specific CTs. We directly evaluated the relationship between chromosome positioning, neighborhood composition, and translocation partner choice in primary lymphocytes, using a cellbased system in which we could induce multiple, concentrated DNA breaks via high-dose irradiation. We critically evaluated mis-rejoining profiles and tested whether breaks occurring nearby were more likely to fuse than breaks occurring at a distance. We show that CT neighborhoods comprise heterologous chromosomes, within which inter-CT distances directly relate to translocation partner choice. These findings demonstrate that interphase chromosome arrangement is a principal factor in genomic instability outcomes in primary lymphocytes, providing a structural context for understanding the biological effects of radiation exposure, and the molecular etiology of tumor-specific translocation patterns

Effects of HIV Infection, methamphetamine dependence and age on cortical thickness, area and volume.

ObjectiveThis study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age.MethodT1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels.ResultsFollowing correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers.ConclusionsMethamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment

Effects of HIV Infection, methamphetamine dependence and age on cortical thickness, area and volume

Objective: This study examined the effects of HIV infection, methamphetamine dependence and their interaction on cortical thickness, area and volume, as well as the potential interactive effects on cortical morphometry of HIV and methamphetamine with age. Method: T1-weighted structural images were obtained on a 3.0T General Electric MR750 scanner. Freesurfer v5.3.0 was used to derive cortical thickness, area and volume measures in thirty-four regions based on Desikan-Killiany atlas labels. Results: Following correction for multiple statistical tests, HIV diagnosis was not significantly related to cortical thickness or area in any ROI, although smaller global cortical area and volume were seen in those with lower nadir CD4 count. HIV diagnosis, nevertheless, was associated with smaller mean cortical volumes in rostral middle frontal gyrus and in the inferior and superior parietal lobes. Methamphetamine dependence was significantly associated with thinner cortex especially in posterior cingulate gyrus, but was not associated with cortical area or volume following correction for multiple statistical tests. We found little evidence that methamphetamine dependence moderated differences in cortical area, volume or thickness for any ROI in the HIV seropositive group. Interactions with age revealed that HIV diagnosis attenuated the degree of age-related cortical thinning seen in non-infected individuals; intercepts indicated that young HIV seropositive individuals had thinner cortex than non-infected peers. Conclusions: Methamphetamine dependence does not appear to potentiate a reduction of cortical area, volume or thickness in HIV seropositive individuals. The finding of thinner cortex in young HIV seropositive individuals and the association between CD4 nadir and global cortical area and volume argue for prioritizing early antiretroviral treatment. Keywords: HIV infection, Methamphetamine dependence, Aging, Cortical thickness, Cortical area, Cortical volum

Neuropsychological comparisons of cocaine versus methamphetamine users: A research synthesis and meta-analysis

<p><i>Background</i>: Previous meta-analytical research examining cocaine and methamphetamine separately suggests potentially different neuropsychological profiles associated with each drug. In addition, neuroimaging studies point to distinct structural changes that might underlie differences in neuropsychological functioning. <i>Objectives</i>: This meta-analysis compared the effect sizes identified in cocaine versus methamphetamine studies across 15 neuropsychological domains. <i>Method</i>: Investigators searched and coded the literature examining the neuropsychological deficits associated with a history of either cocaine or methamphetamine use. A total of 54 cocaine and 41 methamphetamine studies were selected, yielding sample sizes of 1,718 and 1,297, respectively. Moderator analyses were conducted to compare the two drugs across each cognitive domain. <i>Results</i>: Data revealed significant differences between the two drugs. Specifically, studies of cocaine showed significantly larger effect-size estimates (i.e., poorer performance) in verbal working memory when compared to methamphetamine. Further, when compared to cocaine, methamphetamine studies demonstrated significantly larger effect sizes in delayed contextual verbal memory and delayed visual memory. <i>Conclusion</i>: Overall, cocaine and methamphetamine users share similar neuropsychological profiles. However, cocaine appears to be more associated with working memory impairments, which are typically frontally mediated, while methamphetamine appears to be more associated with memory impairments that are linked with temporal and parietal lobe dysfunction.</p