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Poster Session G (+Lunch and Office Hours)

Session Information

Jun 10, 2021 02:35 PM - 03:05 PM(America/Detroit)
Venue : Posters
20210610T1435 20210610T1505 America/Detroit Poster Session G (+Lunch and Office Hours) Posters NIH Common Fund's 2021 High-Risk, High-Reward Research Symposium becky.miller2@nih.gov

Presentations

mDrop-seq: High throughput droplet single-cell RNA-seq of different fungal species reveal transcriptomic differences at single cell level in homogenous populations

High-Throughput and Integrative Biology 02:35 PM - 03:05 PM (America/Detroit) 2021/06/10 18:35:00 UTC - 2021/06/10 19:05:00 UTC
Advances in single-cell RNA sequencing (scRNA-seq) have led to better understanding of heterogeneity in gene expression between individual cells. However, technical challenges like tough cell walls and low RNA quantity have prevented similar profiling of microbial species. We developed microbial Drop-seq (mDrop-seq), a high-throughput scRNA-seq technique on single fungal cells. We demonstrate mDrop-seq's applicability on two yeast species- Saccharomyces cerevisiae, a popular model organism and Candida albicans, a common opportunistic pathogen. We benchmarked mDrop-seq for sensitivity and specificity and used it to profile 35,109 S. cerevisiae cells to detect variation in mRNA levels between cells. As a proof of concept, we quantified expression differences in heat-shocked S. cerevisiae. mDrop-seq detected variations at single cell resolution in the activation of different stress response pathways within seemingly homogenous populations of S. cerevisiae. We also used mDrop-seq to profile single C. albicans cells, a clinically relevant yeast species with thick cell walls. 39,705 C. albicans cells were profiled using mDrop-seq under different conditions, including exposure to fluconazole, a common anti-fungal agent. We noted differential upregulation in stress response and drug target pathways in C. albicans cells with interesting changes in cell cycle patterns. Our experiments are the first single cell RNA-seq of different yeast species at high throughput, demonstrating mDrop-seq as an affordable, easily implementable, and scalable technique in yeasts.

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Presenters Anindita Basu
The University Of Chicago
Co-Authors
RD
Ryan Dohn
University Of Chicago
RB
Rebecca Back
University Of Chicago
BX
Bingqing Xie
University Of Chicago
AS
Alan Selewa
University Of Chicago

The Subcortical Connectome of the Human Default Mode Network

Neuroscience 02:35 PM - 03:05 PM (America/Detroit) 2021/06/10 18:35:00 UTC - 2021/06/10 19:05:00 UTC
The default mode network (DMN) mediates self-awareness and introspection, core components of human consciousness. Therapies to restore consciousness in patients with severe brain injuries have historically targeted subcortical sites to reactivate cortical DMN nodes. However, the subcortical connectome of the DMN has not been fully mapped, and optimal subcortical targets for therapeutic neuromodulation of consciousness have not been identified. Here, we aimed to create a comprehensive map of the DMN's subcortical connectome by combining ultra-high resolution functional and structural datasets with advanced signal processing methods. We analyzed 7 Tesla resting-state functional MRI (rs-fMRI) data from 84 healthy volunteers acquired in the Human Connectome Project. Cortical and subcortical DMN nodes were identified by applying a Nesterov-Accelerated SCAlable and Robust (NASCAR) tensor decomposition method. The subcortical connectivity map was then overlaid on a 100 micron ex vivo MRI dataset for neuroanatomic analysis. The NASCAR method revealed that the central lateral thalamic nuclei, lateral hypothalamic nuclei, and basal forebrain are highly positively interconnected with the cortical DMN. Multiple brainstem arousal nuclei also connected with the DMN, with the strongest correlations observed within the ventral tegmental area and the dorsal and median raphe. We also found that the putamen and globus pallidus are negatively correlated (i.e., anti-correlated) with cortical DMN nodes, providing rs-fMRI evidence for the "mesocircuit hypothesis" of human consciousness, whereby a striatopallidal feedback system modulates anterior forebrain function via disinhibition of the central thalamus. The DMN subcortical connectome identified here advances understanding of the subcortical regions that contribute to human consciousness and can be used to inform the selection of therapeutic targets in clinical trials for patients with disorders of consciousness.
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Presenters Brian Edlow
Massachusetts General Hospital
Co-Authors
JL
Jian Li
Massachusetts General Hospital
WC
William Curley
Massachusetts General Hospital
BG
Bastien Guerin
Massachusetts General Hospital
DD
Darin Dougherty
Massachusetts General Hospital
AD
Adrian Dalca
Massachusetts Institute Of Technology
AH
Andreas Horn
Charite University

Methods for correcting inference based on outcomes predicted by machine learning

Behavioral and Social Science 02:35 PM - 03:05 PM (America/Detroit) 2021/06/10 18:35:00 UTC - 2021/06/10 19:05:00 UTC
Machine learning is now being used across the entire scientific enterprise. Researchers commonly use the predictions from random forests or deep neural networks in downstream statistical analysis as if they were observed data. We show that this approach can lead to extreme bias and uncontrolled variance in downstream statistical models. We propose a statistical adjustment to correct biased inference in regression models using predicted outcomes-regardless of the machine-learning model used to make those predictions.

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Presenters Tyler McCormick
University Of Washington

Probing protein interactions through spectral and diffusional super-resolution microscopy

Molecular and Cellular Biology 02:35 PM - 03:05 PM (America/Detroit) 2021/06/10 18:35:00 UTC - 2021/06/10 19:05:00 UTC
We discuss our recent efforts to develop and apply spectral and diffusional super-resolution microscopy methods to visualize intracellular protein interactions and phase separation processes. In particular, with spectrally resolved single-molecule localization microscopy (SR-SMLM), we unveil rich, nanoscale functional and compositional heterogeneities in live cells and in in vitro systems using fluorescent probes that exhibit shifts in emission spectra under different local environments. With single-molecule displacement/diffusivity mapping (SMdM), we map out intracellular diffusivity with unprecedented spatial resolution and fidelity, and thus unveil the effects of protein net charge and crowding in diffusion and phase-separation processes.

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Presenters
KX
Ke Xu
University Of California, Berkeley

Presynaptic maturation determines activity-dependent eye-specific competition

Neuroscience 02:35 PM - 03:05 PM (America/Detroit) 2021/06/10 18:35:00 UTC - 2021/06/10 19:05:00 UTC
The development of eye-specific connections to the brain is a classic model for investigating activity-dependent synaptic competition and refinement. In mammals, axons from the two eyes overlap and compete for target territory in an activity-dependent process driven by patterned spontaneous retinal activity ("retinal waves"). Disrupting or blocking retinal waves causes eye-specific axon segregation defects, but the ultrastructural basis of activity-dependent synaptogenesis and pruning is unknown. Immature eye-specific synapses are difficult to positively identify within electron microscopy images while diffraction-limited optical imaging methods have low spatial resolution that precludes synapse analysis. Thus, there is a gap in understanding how neural activity shapes the development of synaptic connections from the eyes to the brain. 
To address this challenge, we used volumetric STochastic Optical Reconstruction Microscopy (STORM), a single-molecule localization super-resolution imaging technique, together with eye-specific anterograde tracing and synaptic immunolabeling to measure nanoscale structural properties of tens of thousands of retinogeniculate synapses during eye-specific competition in the mouse. We found that maturing eye-specific synapses in the "correct" territory show developmental increases in presynaptic active zone (AZ) and vesicle-associated proteins with no change in postsynaptic density (PSD) proteins. In contrast, weaker "incorrect" RGC connections have significantly fewer presynaptic vesicle proteins with no change in the PSD. To examine the role of neural activity in synaptic competition, we analyzed synapses in a mutant model with disrupted cholinergic retinal waves and arrested eye-specific axon segregation. Abnormal retinal wave activity disrupted synaptogenesis, prevented the presynaptic maturation of vesicle pools, and reduced the magnitude of eye-specific synaptic competition with no change in synaptic PSD volume. These results show that presynaptic refinement defines activity-dependent eye-specific synaptic competition and provide support for a synaptotropic mechanism of retinogeniculate axon development.

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Presenters
CS
Colenso Speer
University Of Maryland
Co-Authors
CZ
Chenghang Zhang
UNIVERSITY OF MARYLAND

Toward imaging bacterial infection in humans

Infectious Diseases and Immunology 02:35 PM - 03:05 PM (America/Detroit) 2021/06/10 18:35:00 UTC - 2021/06/10 19:05:00 UTC
In recent years several molecular imaging strategies have been developed to image bacteria in human patients. Nuclear approaches, specifically positron emission tomography (PET), affords both sensitive detection and the ability to non-invasively capture infections deep within the body. Two key radiotracer classes have risen to the forefront, including metabolic approaches which target bacterial specific biochemical transformations, and antibiotics which have inherent selectivity for bacteria over mammalian cells. One critical question regarding antibiotic radiotracer clinical application is whether resistance to the antibiotics would abrogate any specific uptake, thus diminishing important features of such a diagnostic test, including the predictive values. We recently developed small molecule PET radiotracers based on the synthetic antibiotic trimethoprim ([11C/18F]-TMP and have shown selectivity of these radiotracers for imaging bacteria over other etiologies such as inflammation and cancer in preclinical models. Here, we tested the in vitro uptake of [11C]-TMP in susceptible bacteria and drug resistant clinical isolates which are frequent causes of human infection (Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa). Both TMP resistant and sensitive bacteria showed similar in vitro uptake, which was surprising. This led us to perform whole genome sequencing of these isolates, identifying the mechanisms of TMP resistance which did not impact radiotracer uptake, and look more broadly into known and annotated whole genome alignments where despite the designation of TMP resistance, uptake of TMP radiotracers could be putatively maintained by the presence of the target native protein bacterial DHFR. Finally, we present several case vignettes of patients who have both TMP sensitive and drug resistant infections in our first-in-human experience with [11C]-TMP. This work underscores the ability of select antibiotic radiotracers to image human infection, which may affect our understanding of human bacterial pathogenesis, infection diagnosis, and antimicrobial drug response. 

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Presenters
MS
Mark Sellmyer
University Of Pennsylvania

Single-Session Interventions for Adolescent Depression in the Context of COVID-19: A Nationwide Randomized-Controlled Trial

Behavioral and Social Science 02:35 PM - 03:05 PM (America/Detroit) 2021/06/10 18:35:00 UTC - 2021/06/10 19:05:00 UTC
Background. The COVID-19 pandemic has caused families nationwide extreme financial hardship, social isolation, and distress. These compounding stressors collectively increase risk for adolescent depression-already the leading cause of disability in youth. However, even before the pandemic, < 50% of youth with depression accessed care, and youth do not uniformly benefit from existing treatments. It is thus critical to identify effective, rapidly-scalable strategies to reduce youth depression, during and beyond the COVID-19 pandemic.
Method. This randomized-controlled trial tested online single-session interventions (SSIs) designed to improved proximal targets (hopelessness, perceived agency) and 3-month depression, anxiety, and COVID-19-related trauma during the COVID-19 pandemic in adolescents with elevated depression symptoms (N=2,452, ages 13-16). Youth living across the United States recruited via social media were randomized to 1 of 3 self-guided SSIs: a behavioral activation SSI (BA-SSI), an SSI teaching growth mindset-the belief that personal traits are malleable (GM-SSI), or a supportive control. We tested each SSI's effects on post-SSI (hopelessness, agency) and 3-month outcomes (depression, generalized anxiety, COVID-related trauma).
Results. Compared to the control, both active SSIs reduced 3-month depressive symptoms (BA: d=.18, p < .001; GM: d=.18, p < .001), reduced post-intervention hopelessness (BA: d=.26, p < .001; GM: d=.30, p < .001) and increased post-intervention perceived agency (BA: d=.36, p < .001; GM: d=0.18, p < .001). The GM-SSI, but not the BA-SSI, reduced 3-month generalized anxiety symptoms (d=.10, p=0.03) and COVID-related trauma (d=.10, p=0.03) versus the control. The BA-SSI outperformed the GM-SSI in strengthening agency (d=.16, p=.001); the GM-SSI outperformed the BA-SSI in reducing generalized anxiety (d=.10, p=.04). 
Conclusions. Results confirm the effectiveness of two free-of-charge, online SSIs for adolescents experiencing depression, even when delivered in the high-stress context of the COVID-19 pandemic.

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Presenters Jessica Schleider
SUNY Stony Brook University
Co-Authors
MM
Michael Mullarkey
Stony Brook University
KF
Kathryn Fox
University Of Denver
MD
Mallory Dobias
Stony Brook University
AS
Akash Shroff
Stony Brook University
CR
Chantelle Roulston
Stony Brook University
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Slides

1623082994JessicaL.Schleider-Single-SessionInterventionsforAdolescentDepression.png
Single-Session Interventions for Adol...
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Submitted by Jessica Schleider
1623081737ColensoSpeer-Presynapticmaturation.png
Presynaptic maturation determines act...
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Submitted by Colenso Speer
1623085987MarkASellmyer-Towardimagingbacterialinfectioninhumans-1.png
Toward imaging bacterial infection in...
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Submitted by Mark Sellmyer
1623090052KeXu-Probingintracellularproteininteractions.png
Probing protein interactions through ...
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Submitted by Ke Xu
1623247604TylerMcCormick-MethodsforCorrecting.png
Methods for correcting inference base...
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Submitted by Tyler McCormick
1623089329Aninditabasu-SingleCellTranscriptomicsinMicrobes-1.png
mDrop-seq: High throughput droplet si...
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Submitted by Anindita Basu
1623080326189_Brian_l._Edlow___Mapping_the_Subcortical_Functional_Connectome_1.png
The Subcortical Connectome of the Hum...
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Submitted by Brian Edlow

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