Learning science alongside peers with intellectual and developmental disabilities.

"Lifelong Learning with Friends" provides diversity training to college students by having them learn science alongside adults with intellectual and developmental disabilities (IDDs). Volunteers showed increased interest in IDD-focused research, social interaction, and advocacy.

Identifying Cellular and Molecular Mechanisms for Magnetosensation.

Diverse animals ranging from worms and insects to birds and turtles perform impressive journeys using the magnetic field of the earth as a cue. Although major cellular and molecular mechanisms for sensing mechanical and chemical cues have been elucidated over the past three decades, the mechanisms that animals use to sense magnetic fields remain largely mysterious. Here we survey progress on the search for magnetosensory neurons and magnetosensitive molecules important for animal behaviors. Emphasis is placed on magnetosensation in insects and birds, as well as on the magnetosensitive neuron pair AFD in the nematode Caenorhabditis elegans. We also review conventional criteria used to define animal magnetoreceptors and suggest how approaches used to identify receptors for other sensory modalities may be adapted for magnetoreceptors. Finally, we discuss prospects for underutilized and novel approaches to identify the elusive magnetoreceptors in animals.

Coronary Artery Calcium Scoring: Current Status and Future Directions.

Coronary artery calcium (CAC) scores obtained from CT scans have been shown to be prognostic in assessment of the risk for development of cardiovascular diseases, facilitating the prediction of outcome in asymptomatic individuals. Currently, several methods to calculate the CAC score exist, and each has its own set of advantages and disadvantages. Agatston CAC scoring is the most extensively used method. CAC scoring is currently recommended for use in asymptomatic individuals to predict the risk of developing cardiovascular diseases and the disease-specific mortality. In specific subsets of patients, the CAC score has also been recommended for reclassifying cardiovascular risk and aiding in decision making when planning primary prevention interventions such as statin therapy. The progression of CAC scores on follow-up images has been shown to be linked to risk of myocardial infarction and cardiovascular mortality. While the CAC score is a validated tool used clinically, several challenges, including various pitfalls associated with the acquisition, calculation, and interpretation of the score, prevent more widespread adoption of this metric. Recent research has been focused extensively on strategies to improve existing scoring methods, including measuring calcium attenuation, detecting microcalcifications, and focusing on extracoronary calcifications, and on strategies to improve image acquisition. A better understanding of CAC scoring approaches will help radiologists and other physicians better use and interpret these scores in their workflows. An invited commentary by S. Gupta is available online. Online supplemental material is available for this article. ©RSNA, 2022.

Collaborative Development of a PACS-Integrated Quality Control Dashboard: a Single Institutional Experience.

Regular communication between technologists and radiologists is necessary for maintaining optimal diagnostic image quality throughout a radiology practice. In a large hospital system with multiple sites, this task becomes increasingly difficult without simultaneously causing significant disruptions in the clinical workflow and decreased throughput. Thus, establishing a system for quality control reporting that enables effective communication in a seamless and convenient manner is imperative. In this report, we describe the development of a new integrated system, in collaboration with our PACS vendor, with tools that allow for instant reporting of quality errors and dashboards providing real-time up-to-date quality data across our hospital system, directly accessible from PACS. To date, 8,167 quality reports have been logged in our new system with roughly 355 submissions per month. Early user engagement and consensus feedback among radiologists and technologists have been positive suggesting an overall improvement from prior systems. We hope this report can help inform other radiology enterprises seeking to improve quality control reporting within their clinical practice.

Long-term activity drives dendritic branch elaboration of a C. elegans sensory neuron.

Neuronal activity often leads to alterations in gene expression and cellular architecture. The nematode Caenorhabditis elegans, owing to its compact translucent nervous system, is a powerful system in which to study conserved aspects of the development and plasticity of neuronal morphology. Here we focus on one pair of sensory neurons, termed URX, which the worm uses to sense and avoid high levels of environmental oxygen. Previous studies have reported that the URX neuron pair has variable branched endings at its dendritic sensory tip. By controlling oxygen levels and analyzing mutants, we found that these microtubule-rich branched endings grow over time as a consequence of neuronal activity in adulthood. We also find that the growth of these branches correlates with an increase in cellular sensitivity to particular ranges of oxygen that is observable in the behavior of older worms. Given the strengths of C. elegans as a model organism, URX may serve as a potent system for uncovering genes and mechanisms involved in activity-dependent morphological changes in neurons and possible adaptive changes in the aging nervous system.

The Past, Present, and Future (Liquid Biopsy) of Serum Tumor Markers in Lung Cancer: A Primer for the Radiologist.

ABSTRACT: Lung cancer continues to be a major cause of death throughout the world. The ability to both accurately diagnose lung cancer in its early stages and monitor response to treatment is essential to reducing the morbidity and mortality associated with the disease. Serum tumor markers have been identified as potential biomarkers that may aid in lung cancer diagnosis and surveillance. These markers, when combined with cross-sectional imaging, may result in more robust screening and surveillance protocols. The future role of serum tumor markers in lung cancer includes the advancement of "liquid biopsies," in which peripheral blood samples are analyzed for tumor components without the need for a tissue biopsy.

Considerations in imaging interpretations for colitis in critically ill patients during the COVID-19 era.

OBJECTIVE: The study aims to demonstrate risk factors for colitis in intensive care unit patients with and without coronavirus disease 2019 (COVID-19). METHODS: Retrospective review was performed to identify intensive care unit (ICU) patients with the diagnosis of COVID-19 with computed tomography (CT) between March 20 and December 31, 2020. ICU patients without COVID-19 diagnosis with CT between March 20 and May 10, 2020 were also identified. CT image findings of colitis or terminal ileitis as well as supportive treatment including ventilator, vasopressors, or extracorporeal membrane oxygenation (ECMO) were recorded. Statistical analysis was performed to determine if clinical factors differed in patients with and without positive CT finding. RESULTS: Total 61 ICU patients were selected, including 32 (52%) COVID-19-positive patients and 29 (48%) non-COVID-19 patients. CT findings of colitis or terminal ileitis were identified in 27 patients (44%). Seventy-four percent of the patients with positive CT findings (20/27) received supportive therapies prior to CT, while 56% of the patients without abnormal CT findings (19/34) received supportive therapies. Vasopressor treatment was significantly associated with development of colitis and/or terminal ileitis (p = 0.04) and COVID-19 status was not significantly different between these groups (p = 0.07). CONCLUSIONS: In our study, there was significant correlation between prior vasopressor therapy and imaging findings of colitis or terminal ileitis in ICU patients, independent of COVID-19 status. Our observation raises a possibility that the reported COVID-19-related severe gastrointestinal complications and potential poor outcome could have been confounded by underlying severe critically ill status, and warrants a caution in diagnosis of gastrointestinal complication.

Quantifying the decrease in emergency department imaging utilization during the COVID-19 pandemic at a multicenter healthcare system in Ohio.

PURPOSE: To illustrate the change in emergency department (ED) imaging utilization at a multicenter health system in the state of Ohio during the COVID-19 pandemic. METHODS: A retrospective observational study was conducted assessing ED imaging volumes between March 1, 2020, and May 11, 2020, during the COVID-19 crisis. A rolling 7-day total value was used for volume tracking and comparison. Total imaging utilization in the ED was compared with new COVID-19 cases in our region. Utilization was first categorized by modality and then by plain films and computed tomography (CT) scans grouped by body part. CT imaging of the chest was specifically investigated by assessing both CT chest only exams and CT chest, abdomen, and pelvis (C/A/P) exams. Ultimately, matching pair-wise statistical analysis of exam volumes was performed to assess significance of volume change. RESULTS: Our multicenter health system experienced a 46% drop in imaging utilization (p < 0.0001) during the pandemic. Matching pair-wise analysis showed a statistically significant volume decrease by each modality and body part. The exceptions were non-contrast chest CT, which increased (p = 0.0053), and non-trauma C/A/P CT, which did not show a statistically significant volume change (p = 0.0633). CONCLUSION: ED imaging utilization trends revealed through actual health system data will help inform evidence-based decisions for more accurate volume predictions and therefore institutional preparedness for current and future pandemics.

A Novel Peptide Restricts Ethanol Modulation of the BK Channel In Vitro and In Vivo.

Alcohol is a widely used and abused substance. A major unresolved issue in the alcohol research field is determining which of the many alcohol target proteins identified to date is responsible for shaping each specific alcohol-related behavior. The large-conductance, calcium- and voltage-activated potassium channel (BK channel) is a conserved target of ethanol. Genetic manipulation of the highly conserved BKα channel influences alcohol-related behaviors across phylogenetically diverse species that include worm, fly, mouse, and man. A pharmacological tool that prevents alcohol's action at a single target, like the BK channel, would complement genetic approaches in the quest to define the behavioral consequences of alcohol at each target. To identify agents that specifically modulate the action of ethanol at the BK channel, we executed a high-throughput phagemid-display screen in combination with a Caenorhabditis elegans behavioral genetics assay. This screen selected a novel nonapeptide, LS10, which moderated acute ethanol intoxication in a BK channel-humanized C. elegans strain without altering basal behavior. LS10's action in vivo was dependent upon BK channel functional activity. Single-channel electrophysiological recordings in vitro showed that preincubation with a submicromolar concentration of LS10 restricted ethanol-induced changes in human BKα channel gating. In contrast, no substantial changes in basal human BKα channel function were observed after LS10 application. The results obtained with the LS10 peptide provide proof-of-concept evidence that a combined phagemid-display/behavioral genetics screening approach can provide novel tools for understanding the action of alcohol at the BK channel and how this, in turn, exerts influence over central nervous system function.

Small molecule modulator of sigma 2 receptor is neuroprotective and reduces cognitive deficits and neuroinflammation in experimental models of Alzheimer's disease.

Accumulating evidence suggests that modulating the sigma 2 receptor (Sig2R) can provide beneficial effects for neurodegenerative diseases. Herein, we report the identification of a novel class of Sig2R ligands and their cellular and in vivo activity in experimental models of Alzheimer's disease (AD). We report that SAS-0132 and DKR-1051, selective ligands of Sig2R, modulate intracellular Ca2+ levels in human SK-N-SH neuroblastoma cells. The Sig2R ligands SAS-0132 and JVW-1009 are neuroprotective in a C. elegans model of amyloid precursor protein-mediated neurodegeneration. Since this neuroprotective effect is replicated by genetic knockdown and knockout of vem-1, the ortholog of progesterone receptor membrane component-1 (PGRMC1), these results suggest that Sig2R ligands modulate a PGRMC1-related pathway. Last, we demonstrate that SAS-0132 improves cognitive performance both in the Thy-1 hAPPLond/Swe+ transgenic mouse model of AD and in healthy wild-type mice. These results demonstrate that Sig2R is a promising therapeutic target for neurocognitive disorders including AD.

Structural Changes Associated with Delayed Dark Adaptation in Age-Related Macular Degeneration.

PURPOSE: To examine the relationship between dark adaptation (DA) and optical coherence tomography (OCT)-based macular morphology in age-related macular degeneration (AMD). DESIGN: Prospective, cross-sectional study. PARTICIPANTS: Patients with AMD and a comparison group (>50 years) without any vitreoretinal disease. METHODS: All participants were imaged with spectral-domain OCT and color fundus photographs, and then staged for AMD (Age-related Eye Disease Study system). Both eyes were tested with the AdaptDx (MacuLogix, Middletown, PA) DA extended protocol (20 minutes). A software program was developed to map the DA testing spot (2° circle, 5° superior to the fovea) to the OCT B-scans. Two independent graders evaluated the B-scans within this testing spot, as well as the entire macula, recording the presence of several AMD-associated abnormalities. Multilevel mixed-effects models (accounting for correlated outcomes between 2 eyes) were used for analyses. MAIN OUTCOME MEASURES: The primary outcome was rod-intercept time (RIT), defined in minutes, as a continuous variable. For subjects unable to reach RIT within the 20 minutes of testing, the value of 20 was assigned. RESULTS: We included 137 eyes (n = 77 subjects), 72.3% (n = 99 eyes) with AMD and the remainder belonging to the comparison group. Multivariable analysis revealed that even after adjusting for age and AMD stage, the presence of any abnormalities within the DA testing spot (ß = 4.8, P < 0.001), as well as any abnormalities in the macula (ß = 2.4, P = 0.047), were significantly associated with delayed RITs and therefore impaired DA. In eyes with no structural changes within the DA testing spot (n = 76, 55.5%), the presence of any abnormalities in the remaining macula was still associated with delayed RITs (ß = 2.00, P = 0.046). Presence of subretinal drusenoid deposits and ellipsoid zone disruption were a consistent predictor of RIT, whether located within the DA testing spot (P = 0.001 for both) or anywhere in the macula (P < 0.001 for both). Within the testing spot, the presence of classic drusen or serous pigment epithelium detachment was also significantly associated with impairments in DA (P ≤ 0.018). CONCLUSIONS: Our results suggest a significant association between macular morphology evaluated by OCT and time to dark-adapt. Subretinal drusenoid deposits and ellipsoid zone changes seem to be strongly associated with impaired dark adaptation.

Non-apoptotic role of EGL-1 in exopher production and neuronal health in Caenorhabditis elegans.

While traditionally studied for their pro-apoptotic functions, recent research suggests BH3-only proteins also have non-apoptotic roles. Here, we find that EGL-1, the BH3-only protein in Caenorhabditis elegans, promotes the cell-autonomous production of exophers in adult neurons. Exophers are large, micron-scale vesicles that are ejected from the cell and contain cellular components such as mitochondria. EGL-1 facilitates exopher production potentially through regulation of mitochondrial dynamics. Moreover, an endogenous, low level of EGL-1 expression appears to benefit dendritic health. Our findings provide insights into the mechanistic role of BH3-only protein in mitochondrial dynamics, downstream exopher production, and ultimately neuronal health.

Natural variation in protein kinase D modifies alcohol sensitivity in Caenorhabditis elegans.

Differences in naïve alcohol sensitivity between individuals are a strong predictor of later life alcohol use disorders (AUD). However, the genetic bases for alcohol sensitivity (beyond ethanol metabolism) and pharmacological approaches to modulate alcohol sensitivity remain poorly understood. We used a high-throughput behavioral screen to measure acute behavioral sensitivity to alcohol, a model of intoxication, in a genetically diverse set of over 150 wild strains of the nematode Caenorhabditis elegans. We performed a genome-wide association study to identify loci that underlie natural variation in alcohol sensitivity. We identified five quantitative trait loci (QTL) and further show that variants in the C. elegans ortholog of protein kinase D, dkf-2, likely underlie the chromosome V QTL. We found that resistance to intoxication was conferred by dkf-2 loss-of-function mutations as well as partly by a PKD inhibitor in a dkf-2-dependent manner. Protein kinase D might represent a conserved, druggable target to modify alcohol sensitivity with application towards AUD.

Suppressing APOE4-induced mortality and cellular damage by targeting VHL.

Mortality rate increases with age and can accelerate upon extrinsic or intrinsic damage to individuals. Identifying factors and mechanisms that curb population mortality rate has wide-ranging implications. Here, we show that targeting the VHL-1 (Von Hippel-Lindau) protein suppresses C. elegans mortality caused by distinct factors, including elevated reactive oxygen species, temperature, and APOE4, the genetic variant that confers high risks of neurodegeneration in Alzheimer's diseases and all-cause mortality in humans. These mortality factors are of different physical-chemical nature, yet result in similar cellular dysfunction and damage that are suppressed by deleting VHL-1. Stabilized HIF-1 (hypoxia inducible factor), a transcription factor normally targeted for degradation by VHL-1, recapitulates the protective effects of deleting VHL-1. HIF-1 orchestrates a genetic program that defends against mitochondrial abnormalities, excess oxidative stress, cellular proteostasis dysregulation, and endo-lysosomal rupture, key events that lead to mortality. Genetic Vhl inhibition also alleviates cerebral vascular injury and synaptic lesions in APOE4 mice, supporting an evolutionarily conserved mechanism. Collectively, we identify the VHL-HIF axis as a potent modifier of APOE4 and mortality and propose that targeting VHL-HIF in non-proliferative animal tissues may suppress tissue injuries and mortality by broadly curbing cellular damage.

The Promise of an Evolutionary Perspective of Alcohol Consumption.

The urgent need for medical treatments of alcohol use disorders has motivated the search for novel molecular targets of alcohol response. Most studies exploit the strengths of lab animals without considering how these and other species may have adapted to respond to alcohol in an ecological context. Here, we provide an evolutionary perspective on the molecular and genetic underpinnings of alcohol consumption by reviewing evidence that alcohol metabolic enzymes have undergone adaptive evolution at 2 evolutionary junctures: first, to enable alcohol consumption accompanying the advent of a frugivorous diet in a primate ancestor, and second, to decrease the likelihood of excessive alcohol consumption concurrent with the spread of agriculture and fermentation in East Asia. By similarly considering how diverse vertebrate and invertebrate species have undergone natural selection for alcohol responses, novel conserved molecular targets of alcohol are likely be discovered that may represent promising therapeutic targets.

Clinical Implementation of an Artificial Intelligence Tool in the Detection and Management of Pneumothoraces in Patients With COVID-19.

In this report, we present a series involving critically ill patients with known coronavirus disease (COVID-19) infection where a portable X-ray machine equipped with artificial intelligence (AI) software aided in the urgent radiographic diagnosis of pneumothorax. These cases demonstrate how real-world clinical employment of AI tools capable of analyzing and prioritizing studies in the radiologist's worklist can potentially lead to earlier detection of emergent findings like pneumothorax. The use of AI tools in this manner has the potential to both improve radiology workflow and add significant clinical value in managing critically ill patient populations, such as those with severe COVID-19 infection.

mScarlet and split fluorophore mScarlet resources for plasmid-based CRISPR/Cas9 knock-in in C. elegans.

Fluorescent proteins allow the expression of a gene and the behavior of its protein product to be observed in living animals. The ability to create endogenous fluorescent protein tags via CRISPR genome engineering has revolutionized the authenticity of this expression, and mScarlet is currently our first-choice red fluorescent protein (RFP) for visualizing gene expression in vivo . Here, we have cloned versions of mScarlet and split fluorophore mScarlet previously optimized for C. elegans into the SEC-based system of plasmids for CRISPR/Cas9 knock-in. Ideally, an endogenous tag will be easily visible while not interfering with the normal expression and function of the targeted protein. For low molecular weight proteins that are a fraction of the size of a fluorescent protein tag (e.g. GFP or mCherry) and/or proteins known to be non-functional when tagged in this way, split fluorophore tagging could be an alternative. Here, we used CRISPR/Cas9 knock-in to tag three such proteins with split-fluorophore wrmScarlet: HIS-72, EGL-1, and PTL-1. Although we find that split fluorophore tagging does not disrupt the function of any of these proteins, we were unfortunately unable to observe the expression of most of these tags with epifluorescence, suggesting that split fluorophore tags are often very limited as endogenous reporters. Nevertheless, our plasmid toolkit provides a new resource that enables straightforward knock-in of either mScarlet or split mScarlet in C. elegans.

Evoking natural thermal perceptions using a thin-film thermoelectric device with high cooling power density and speed.

Multimodal sensory feedback from upper-limb prostheses can increase their function and usability. Here we show that intuitive thermal perceptions during cold-object grasping with a prosthesis can be restored in a phantom hand through targeted nerve stimulation via a wearable thin-film thermoelectric device with high cooling power density and speed. We found that specific regions of the residual limb, when thermally stimulated, elicited thermal sensations in the phantom hand that remained stable beyond 48 weeks. We also found stimulation sites that selectively elicited sensations of temperature, touch or both, depending on whether the stimulation was thermal or mechanical. In closed-loop functional tasks involving the identification of cold objects by amputees and by non-amputee participants, and compared with traditional bulk thermoelectric devices, the wearable thin-film device reliably elicited cooling sensations that were up to 8 times faster and up to 3 times greater in intensity while using half the energy and 1/600th the mass of active thermoelectric material. Wearable thin-film thermoelectric devices may allow for the non-invasive restoration of thermal perceptions during touch.

Transgenerational effects of alcohol on behavioral sensitivity to alcohol in Caenorhabditis elegans.

Alcohol abuse and dependence have a substantial heritable component. Although the genome has been considered the sole vehicle of heritable phenotypes, recent studies suggest that drug or alcohol exposure may induce alterations in gene expression that are transmitted across generations. Still, the transgenerational impact of alcohol use (and abuse) remains largely unexplored in part because multigenerational studies using rodent models present challenges for time, sample size, and genetic heterogeneity. Here, we took advantage of the extremely short generation time, large broods, and clonal form of reproduction of the nematode Caenorhabditis elegans. We developed a model of pre-fertilization parental alcohol exposure to test alterations in behavioral responses to acute alcohol treatment (referred to in short as intoxication) in subsequent F1, F2 and F3 generations. We found that chronic and intermittent alcohol-treatment paradigms resulted in opposite changes to intoxication sensitivity of F3 progeny that were only apparent when controlling for yoked trials. Chronic alcohol-treatment paradigm in the parental generation resulted in alcohol-naïve F3 progeny displaying moderate resistance to intoxication. Intermittent treatment resulted in alcohol-naïve F3 progeny displaying moderate hypersensitivity to intoxication. Further study of these phenomena using this new C. elegans model may yield mechanistic insights into how transgenerational effects may occur in other animals.

Applications of the pipeline environment for visual informatics and genomics computations.

BACKGROUND: Contemporary informatics and genomics research require efficient, flexible and robust management of large heterogeneous data, advanced computational tools, powerful visualization, reliable hardware infrastructure, interoperability of computational resources, and detailed data and analysis-protocol provenance. The Pipeline is a client-server distributed computational environment that facilitates the visual graphical construction, execution, monitoring, validation and dissemination of advanced data analysis protocols. RESULTS: This paper reports on the applications of the LONI Pipeline environment to address two informatics challenges - graphical management of diverse genomics tools, and the interoperability of informatics software. Specifically, this manuscript presents the concrete details of deploying general informatics suites and individual software tools to new hardware infrastructures, the design, validation and execution of new visual analysis protocols via the Pipeline graphical interface, and integration of diverse informatics tools via the Pipeline eXtensible Markup Language syntax. We demonstrate each of these processes using several established informatics packages (e.g., miBLAST, EMBOSS, mrFAST, GWASS, MAQ, SAMtools, Bowtie) for basic local sequence alignment and search, molecular biology data analysis, and genome-wide association studies. These examples demonstrate the power of the Pipeline graphical workflow environment to enable integration of bioinformatics resources which provide a well-defined syntax for dynamic specification of the input/output parameters and the run-time execution controls. CONCLUSIONS: The LONI Pipeline environment http://pipeline.loni.ucla.edu provides a flexible graphical infrastructure for efficient biomedical computing and distributed informatics research. The interactive Pipeline resource manager enables the utilization and interoperability of diverse types of informatics resources. The Pipeline client-server model provides computational power to a broad spectrum of informatics investigators--experienced developers and novice users, user with or without access to advanced computational-resources (e.g., Grid, data), as well as basic and translational scientists. The open development, validation and dissemination of computational networks (pipeline workflows) facilitates the sharing of knowledge, tools, protocols and best practices, and enables the unbiased validation and replication of scientific findings by the entire community.