Faculty Bibliography

A premature truncation of MYBPHL in humans and a loss of Mybphl in mice is associated with dilated cardiomyopathy, atrial and ventricular arrhythmias, and atrial enlargement. MYBPHL encodes myosin binding protein H-like (MyBP-HL). Prior work in mice indirectly identified Mybphl expression in the atria and in small puncta throughout the ventricle. Because of its genetic association with human and mouse cardiac conduction system disease, we evaluated the anatomical localization of MyBP-HL and the consequences of loss of MyBP-HL on conduction system function. Immunofluorescence microscopy of normal adult mouse ventricles identified MyBP-HL-positive ventricular cardiomyocytes that co-localized with the ventricular conduction system marker contactin-2 near the atrioventricular node and in a subset of Purkinje fibers. Mybphl heterozygous ventricles had a marked reduction of MyBP-HL-positive cells compared to controls. Lightsheet microscopy of normal perinatal day 5 mouse hearts showed enrichment of MyBP-HL-positive cells within and immediately adjacent to the contactin-2-positive ventricular conduction system, but this association was not apparent in Mybphl heterozygous hearts. Surface telemetry of Mybphl-null mice revealed atrioventricular block and atrial bigeminy, while intracardiac pacing revealed a shorter atrial relative refractory period and atrial tachycardia. Calcium transient analysis of isolated Mybphl-null atrial cardiomyocytes demonstrated an increased heterogeneity of calcium release and faster rates of calcium release compared to wild type controls. Super-resolution microscopy of Mybphl heterozygous and homozygous null atrial cardiomyocytes showed ryanodine receptor disorganization compared to wild type controls. Abnormal calcium release, shorter atrial refractory period, and atrial dilation seen in Mybphl null, but not wild type control hearts, agree with the observed atrial arrhythmias, bigeminy, and atrial tachycardia, whereas the proximity of MyBP-HL-positive cells with the ventricular conduction system provides insight into how a predominantly atrial expressed gene contributes to ventricular arrhythmias and ventricular dysfunction.

Brain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. Our unbiased proteomics analysis of melanoma short-term cultures revealed that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. We showed that melanoma cells require amyloid beta (AB) for growth and survival in the brain parenchyma. Melanoma-secreted AB activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype and prevents phagocytosis of melanoma by microglia. Finally, we demonstrate that pharmacological inhibition of AB decreases brain metastatic burden.

Background: Stressor exposure is common in daily life where decisions involving uncertainty are made, yet the effects of stress on such decisions are equivocal across the literature. One reason for this is because research rarely dissociates between decisions involving risk (known outcome probabilities) and those involving ambiguity (unknown probabilities). Stress is thought to render appraisals of ambiguity more negative, but little work has examined if real-world stressor exposure differentially affect decisions involving risk vs. ambiguity.
Method(s): Across two studies, we used a comprehensive lifetime stressor inventory (Stress and Adversity Inventory for Adults) and a standard economic approach to quantify risk and ambiguity tolerance. Participants made 240 binary choices between a certain gain ($5) and a lottery option where they could win Result(s): In Study 1 (N=58), total stressor count and severity were each negatively correlated with the proportion of ambiguous lottery choices individuals were willing to accept (count: r=-0.33,p=0.01; severity: r=-0.39,p=0.002; Spearman's rho). In contrast, no relation emerged for risky choices (count: r=0.002,p=0.98; severity: r=-0.08,p=0.51). These ambiguity-selective effects were replicated in a second study (N=188) using regression analyses while controlling for age, gender, income and mental health (count: s=-0.25,SE=0.011,p=0.02; severity: s=-0.29,SE=0.011,p=0.01).
Conclusion(s): Participants experiencing greater lifetime stress were more averse to decisions involving ambiguity, but not risk. Our findings identify cumulative stressor exposure as a novel factor that is uniquely associated with a lower willingness to engage in explicit forms of decisions under uncertainty. Supported By: NIH Grant R01DA038063 (PWG) NIH Grant 5R01DA038063 (PWG) NIH Grant F32MH110135 (CMR) NIH Grant K08 MH103443 (GMS) NARSAD Young Investigator Grant (Brain and Behavior Foundation) (CMR) NARSAD Young Investigator Grant (Brain and Behavior Foundation) (GMS) Society in Science-Branco Weiss Fellowship (GMS) Keywords: Stress, Decision-Making, Ambiguity, Early Life Stress
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Dendrites are elaborate neural processes which integrate inputs from various sources in space and time. While decades of work have suggested an independent role for dendrites in driving nonlinear computations for the cell, only recently have technological advances enabled us to capture the variety of activity in dendrites and their coupling dynamics with the soma. Under certain circumstances, activity generated in a given dendritic branch remains isolated, such that the soma or even sister dendrites are not privy to these localized signals. Such branch-specific activity could radically increase the capacity and flexibility of coding for the cell as a whole. Here, we discuss these forms of localized and branch-specific activity, their functional relevance in plasticity and behavior, and their supporting biophysical and circuit-level mechanisms. We conclude by showcasing electrical and optical approaches in hippocampal area CA3, using original experimental data to discuss experimental and analytical methodology and key considerations to take when investigating the functional relevance of independent dendritic activity.

PURPOSE/OBJECTIVE:, and proton density) and sodium density weighted images over the whole brain. METHODS:were evaluated in phantoms. Finally, in vivo application of the method was demonstrated in five healthy subjects. RESULTS:values measured using our method were lower than the results measured by other conventional techniques. CONCLUSIONS:

INTRODUCTION/BACKGROUND:Neurological complications among hospitalized COVID-19 patients may be associated with elevated neurodegenerative biomarkers. METHODS:Among hospitalized COVID-19 patients without a history of dementia (N = 251), we compared serum total tau (t-tau), phosphorylated tau-181 (p-tau181), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), and amyloid beta (Aβ40,42) between patients with or without encephalopathy, in-hospital death versus survival, and discharge home versus other dispositions. COVID-19 patient biomarker levels were also compared to non-COVID cognitively normal, mild cognitive impairment (MCI), and Alzheimer's disease (AD) dementia controls (N = 161). RESULTS:Admission t-tau, p-tau181, GFAP, and NfL were significantly elevated in patients with encephalopathy and in those who died in-hospital, while t-tau, GFAP, and NfL were significantly lower in those discharged home. These markers correlated with severity of COVID illness. NfL, GFAP, and UCHL1 were higher in COVID patients than in non-COVID controls with MCI or AD. DISCUSSION/CONCLUSIONS:Neurodegenerative biomarkers were elevated to levels observed in AD dementia and associated with encephalopathy and worse outcomes among hospitalized COVID-19 patients.

PURPOSE/OBJECTIVE:To present a novel 3T 24-channel glove array that enables hand and wrist imaging in varying postures. METHODS:The glove array consists of an inner glove holding the electronics and an outer glove protecting the components. The inner glove consists of four main structures: palm, fingers, wrist, and a flap that rolls over on top. Each structure was constructed out of three layers: a layer of electrostatic discharge flame-resistant fabric, a layer of scuba neoprene, and a layer of mesh fabric. Lightweight and flexible high impedance coil (HIC) elements were inserted into dedicated tubes sewn into the fabric. Coil elements were deliberately shortened to minimize the matching interface. Siemens Tim 4G technology was used to connect all 24 HIC elements to the scanner with only one plug. RESULTS:The 24-channel glove array allows large motion of both wrist and hand while maintaining the SNR needed for high-resolution imaging. CONCLUSION/CONCLUSIONS:In this work, a purpose-built 3T glove array that embeds 24 HIC elements is demonstrated for both hand and wrist imaging. The 24-channel glove array allows a great range of motion of both the wrist and hand while maintaining a high SNR and providing good theoretical acceleration performance, thus enabling hand and wrist imaging at different postures to extract kinematic information.

Neurotransmitters and neuromodulators have a wide range of key roles throughout the nervous system. However, their dynamics in both health and disease have been challenging to assess, owing to the lack of in vivo tools to track them with high spatiotemporal resolution. Thus, developing a platform that enables minimally invasive, large-scale and long-term monitoring of neurotransmitters and neuromodulators with high sensitivity, high molecular specificity and high spatiotemporal resolution has been essential. Here, we review the methods available for monitoring the dynamics of neurotransmitters and neuromodulators. Following a brief summary of non-genetically encoded methods, we focus on recent developments in genetically encoded fluorescent indicators, highlighting how these novel indicators have facilitated advances in our understanding of the functional roles of neurotransmitters and neuromodulators in the nervous system. These studies present a promising outlook for the future development and use of tools to monitor neurotransmitters and neuromodulators.

OBJECTIVE:The aim of this study was to examine effects of radiation therapy (RT) for head and neck cancer (HNC) on periodontal disease and relationships to caries. STUDY DESIGN/METHODS:A multicenter prospective observational cohort study (OraRad) was conducted in patients undergoing RT for HNC. Assessments were conducted by calibrated examiners at the pre-RT (baseline) visit (n = 533), the 12-month visit (n = 414), and the 24-month visit (n = 365). RESULTS:The average whole mouth mean (standard error (SE)) distance from the cementoenamel junction to the gingival margin (CEJ-GM) decreased significantly from 0.43 (0.04) mm at baseline to 0.24 (0.04) mm at 12 months and 0.11 (0.04) mm at 24 months (P ≤ .001). Whole mouth mean (SE) percentage of sites with CEJ-GM distance of <0 mm increased significantly from 23.3% (1.0%) at baseline to 28.5% (1.0%) at 12 months and 30.5% (1.1%) at 24 months (P ≤ .02). Higher mean radiation dose to the mandible was associated with a greater increase in the percentage of mandibular sites with CEJ-GM distance of <0 mm (P = .003). Both mean CEJ-GM distance and the percentage of sites with a CEJ-GM distance <0 mm were strongly associated with whole mouth mean proportion of decayed, missing, and filled surfaces, as well as proportion of decayed or filled facial/buccal surfaces specifically, (P < .001), with greater gingival recession associated with increased caries. CONCLUSIONS:RT for HNC leads to mandibular gingival recession in a dose-dependent manner. This gingival recession may contribute to increased risk for cervical caries seen in these patients.

PURPOSE OF REVIEW/OBJECTIVE:In this review, we report on new findings regarding associations of uric acid with kidney health. We discuss kidney stones, effects of uric acid in chronic kidney disease (CKD), and management of gout in CKD. Recent studies on neuroprotective effects of raising uric acid provide interesting data regarding nephrolithiasis. RECENT FINDINGS/RESULTS:Elevated urate levels have been implicated in the progression of chronic kidney disease (CKD), but the results from PERL and CKD-FIX studies did not demonstrate that allopurinol slowed CKD progression. The SURE-PD3 sought to determine if increasing uric acid would slow the progression of Parkinson's disease. Results ultimately did not support this hypothesis, but high urinary uric acid levels caused uric acid stones, not calcium stones. Low urinary pH remains the key to the formation of uric acid stones. Thiazolidinediones improve insulin resistance, which is associated with an increase in urine pH. The most recent research has not supported the hypothesis that lowering serum uric acid levels will slow the progression of CKD or provide neuroprotection in Parkinson's disease. It is still unclear as to why uric acid stone formers have a high net acid excretion. The STOP-GOUT trial demonstrates that there was a lack of significant adverse events with higher urate-lowering dosages of allopurinol and febuxostat, despite patients' kidney function. This may push other studies to administer higher dosages per ACR guidelines. Future studies could then demonstrate decreased progression of CKD.