Faculty Bibliography

A 10-year-old girl presented with ileus, urinary retention, dry mouth, lack of tears, fixed dilated pupils, and diffuse anhidrosis 7-days after a febrile illness. We hypothesized that her syndrome was due to autoimmunity against muscarinic acetylcholine receptors, blocking their activation. Using an indirect enzyme-linked immunosorbent assay for all five muscarinic receptors (M₁ -M₅ ) we identified in the patient's serum antibodies that selectively bound to M₃ receptors. In-vitro functional studies confirmed that these autoantibodies selectively blocked M₃ receptor activation. Thus, autoantibodies against M₃ acetylcholine receptors can cause acute postganglionic cholinergic dysautonomia. This article is protected by copyright. All rights reserved.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

In this study, we investigate the feasibility of using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI), diffusion weighted imaging (DWI), and dynamic positron emission tomography (PET) for detection of metastatic lymph nodes in head and neck squamous cell carcinoma (HNSCC) cases. Twenty HNSCC patients scheduled for lymph node dissection underwent DCE-MRI, dynamic PET, and DWI using a PET-MR scanner within one week prior to their planned surgery. During surgery, resected nodes were labeled to identify their nodal levels and sent for routine clinical pathology evaluation. Quantitative parameters of metastatic and normal nodes were calculated from DCE-MRI (v_e, v_p, PS, F_p, K^trans), DWI (ADC) and PET (K_i, K₁, k₂, k₃) to assess if an individual or a combination of parameters can classify normal and metastatic lymph nodes accurately. There were 38 normal and 11 metastatic nodes covered by all three imaging methods and confirmed by pathology. 34% of all normal nodes had volumes greater than or equal to the smallest metastatic node while 4 normal nodes had SUV > 4.5. Among the MRI parameters, the median v_p, F_p, PS, and K^trans values of the metastatic lymph nodes were significantly lower (p = <0.05) than those of normal nodes. v_e and ADC did not show any statistical significance. For the dynamic PET parameters, the metastatic nodes had significantly higher k₃ (p value = 8.8 × 10^-8) and K_i (p value = 5.3 × 10^-8) than normal nodes. K₁ and k₂ did not show any statistically significant difference. K_i had the best separation with accuracy = 0.96 (sensitivity = 1, specificity = 0.95) using a cutoff of K_i = 5.3 × 10^-3 mL/cm³/min, while k₃ and volume had accuracy of 0.94 (sensitivity = 0.82, specificity = 0.97) and 0.90 (sensitivity = 0.64, specificity = 0.97) respectively. 100% accuracy can be achieved using a multivariate logistic regression model of MRI parameters after thresholding the data with K_i < 5.3 × 10^-3 mL/cm³/min. The results of this preliminary study suggest that quantitative MRI may provide additional value in distinguishing metastatic nodes, particularly among small nodes, when used together with FDG-PET.

While Hox genes encode for conserved transcription factors (TFs), they are further divided into anterior, central, and posterior groups based on their DNA-binding domain similarity. The posterior Hox group expanded in the deuterostome clade and patterns caudal and distal structures. We aim to address how similar HOX TFs diverge to induce different positional identities. We studied HOX TF DNA-binding and regulatory activity during an in vitro motor neuron differentiation system that recapitulates embryonic development. We find diversity in the genomic binding profiles of different HOX TFs, even among the posterior group paralogs that share similar DNA binding domains. These differences in genomic binding are explained by differing abilities to bind to previously inaccessible sites. For example, the posterior group HOXC9 has a greater ability to bind occluded sites than the posterior HOXC10, producing different binding patterns and driving differential gene expression programs. From these results, we propose that the differential abilities of posterior HOX TFs to bind to previously inaccessible chromatin drive patterning diversification.

Controlling the release or uptake of (bio-) molecules and drugs from liposomes is critically important for a range of applications in bioengineering, synthetic biology, and drug delivery. In this paper, we report how the reversible photoswitching of synthetic lipid bilayer membranes made from azobenzene-containing phosphatidylcholine (azo-PC) molecules (photolipids) leads to increased membrane permeability. We show that cell-sized, giant unilamellar vesicles (GUVs) prepared from photolipids display leakage of fluorescent dyes after irradiation with UV-A and visible light. Langmuir-Blodgett and patch-clamp measurements show that the permeability is the result of transient pore formation. By comparing the trans-to-cis and cis-to-trans isomerization process, we find that this pore formation is the result of area fluctuations and a change of the area cross-section between both photolipid isomers.

Patterns of functional connectivity are unique at the individual level, enabling test-retest matching algorithms to identify a subject from among a group using only their functional connectome. Recent findings show that accuracies of these algorithms in children increase with age. Relatedly, the persistence of functional connectivity (FC) patterns across tasks and rest also increases with age. This study investigated the hypothesis that within-subject stability and between-subject similarity of the whole-brain pediatric connectome are developmentally relevant outcomes. Using data from 210 help-seeking children and adolescents, ages 6-21 years (Healthy Brain Network Biobank), we computed whole-brain FC matrices for each participant during two different movies (MovieDM and MovieTP) and two runs of task-free rest (all from a single scan session) and fed these matrices to a test-retest matching algorithm. We replicated the finding that matching accuracies for children and youth (ages 6-21 years) are low (18-44%), and that cross-state and cross-movie accuracies were the lowest. Results also showed that parcellation resolution and the number of volumes used in each matrix affect fingerprinting accuracies. Next, we calculated three measures of whole-connectome stability for each subject: cross-rest (Rest1-Rest2), cross-state (MovieDM-Rest1), and cross-movie (MovieDM-MovieTP), and three measures of within-state between-subject connectome similarity for Rest1, MovieDM, and MovieTP. We show that stability and similarity were correlated, but that these measures were not related to age. A principal component analysis of these measures yielded two components that we used to test for brain-behavior correlations with IQ, general psychopathology, and social skills measures (n = 119). The first component was significantly correlated with the social skills measure (r=-0.26, p = 0.005). Post hoc correlations showed that the social skills measure correlated with both cross-rest stability (r=-0.29, p = 0.001) and with connectome similarity during MovieDM (r=-0.28, p = 0.002). These findings suggest that the stability and similarity of the whole-brain connectome relate to the development of social skills. We infer that the maturation of the functional connectome simultaneously achieves patterns of FC that are distinct at the individual subject level, that are shared across individuals, and that are persistent across states and across runs-features which presumably combine to optimize neural processing during development. Future longitudinal work could reveal the developmental trajectories of stability and similarity of the connectome.

The vestibular system broadcasts head-movement-related signals to sensory areas throughout the brain, including visual cortex. These signals are crucial for the brain's ability to assess whether motion of the visual scene results from the animal's head movements. However, how head movements affect visual cortical circuits remains poorly understood. Here, we discover that ambient luminance profoundly transforms how mouse primary visual cortex (V1) processes head movements. While in darkness, head movements result in overall suppression of neuronal activity; in ambient light, the same head movements trigger excitation across all cortical layers. This light-dependent switch in how V1 processes head movements is controlled by somatostatin-expressing (SOM) inhibitory neurons, which are excited by head movements in dark, but not in light. This study thus reveals a light-dependent switch in the response of V1 to head movements and identifies a circuit in which SOM cells are key integrators of vestibular and luminance signals.

Enhancing repair of myelin is an important therapeutic goal in many neurological disorders characterized by demyelination. In the healthy adult brain, ventral neural stem cells (vNSCs) in the subventricular zone, marked by GLI1 expression, do not generate oligodendrocytes. However, in response to demyelination, their progeny are recruited to lesions where they differentiate into oligodendrocytes and ablation of GLI1 further enhances remyelination. GLI1 and GLI2 are closely related transcriptional activators but the role of GLI2 in remyelination by vNSCs is not clear. Here, we show that genetic ablation of Gli1 in vNSCs increases GLI2 expression and combined loss of both transcription factors decreases the recruitment and differentiation of their progeny in demyelinated lesions. These results indicate that GLI1 and GLI2 have distinct, non-redundant functions in vNSCs and their relative levels play an essential role in the response to demyelination.

Alzheimer's disease (AD) is the most common form of dementia. Despite many years of intense research, there is currently still no effective treatment. Multiple cell types contribute to disease pathogenesis, with an increasing body of data pointing to the active participation of astrocytes. Astrocytes play a pivotal role in the physiology and metabolic functions of neurons and other cells in the central nervous system. Because of their interactions with other cell types, astrocyte functions must be understood in their biologic context, thus many studies have used mouse models, of which there are over 190 available for AD research. However, none appear able to fully recapitulate the many functional changes in astrocytes reported in human AD brains. Our review summarizes the observations of astrocyte biology noted in mouse models of familial and sporadic AD. The limitations of AD mouse models will be discussed and current attempts to overcome these disadvantages will be described. With increasing understanding of the non-neuronal contributions to disease, the development of new methods and models will provide further insights and address important questions regarding the roles of astrocytes and other non-neuronal cells in AD pathophysiology. The next decade will prove to be full of exciting opportunities to address this devastating disease.

PURPOSE/OBJECTIVE:This study reports on the development of a novel 3D procedure planning technique to provide pre-ablation treatment planning for partial gland prostate cryoablation (cPGA). METHODS:Twenty men scheduled for partial gland cryoablation (cPGA) underwent pre-operative image segmentation and 3D modeling of the prostatic capsule, index lesion, urethra, rectum, and neurovascular bundles based upon multi-parametric MRI data. Pre-treatment 3D planning models were designed including virtual 3D cryotherapy probes to predict and plan cryotherapy probe configuration needed to achieve confluent treatment volume. Treatment efficacy was measured with 6 month post-operative MRI, serum prostate specific antigen (PSA) at 3 and 6 months, and treatment zone biopsy results at 6 months. Outcomes from 3D planning were compared to outcomes from a series of 20 patients undergoing cPGA using traditional 2D planning techniques. RESULTS:Forty men underwent cPGA. The median age of the cohort undergoing 3D treatment planning was 64.8 years with a median pretreatment PSA of 6.97 ng/mL. The Gleason grade group (GGG) of treated index lesions in this cohort included 1 (5%) GGG1, 11 (55%) GGG2, 7 (35%) GGG3, and 1 (5%) GGG4. Two (10%) of these treatments were post-radiation salvage therapies. The 2D treatment cohort included 20 men with a median age of 68.5 yrs., median pretreatment PSA of 6.76 ng/mL. The Gleason grade group (GGG) of treated index lesions in this cohort included 3 (15%) GGG1, 8 (40%) GGG2, 8 (40%) GGG3, 1 (5%) GGG4. Two (10%) of these treatments were post-radiation salvage therapies. 3D planning predicted the same number of cryoprobes for each group, however a greater number of cryoprobes was used in the procedure for the prospective 3D group as compared to that with 2D planning (4.10 ± 1.37 and 3.25 ± 0.44 respectively, p = 0.01). At 6 months post cPGA, the median PSA was 1.68 ng/mL and 2.38 ng/mL in the 3D and 2D cohorts respectively, with a larger decrease noted in the 3D cohort (75.9% reduction noted in 3D cohort and 64.8% reduction 2D cohort, p 0.48). In-field disease detection was 1/14 (7.1%) on surveillance biopsy in the 3D cohort and 3/14 (21.4%) in the 2D cohort, p = 0.056) In the 3D cohort, 6 month biopsy was not performed in 4 patients (20%) due to undetectable PSA, negative MRI, and negative MRI Axumin PET. For the group with traditional 2D planning, treatment zone biopsy was positive in 3/14 (21.4%) of the patients, p = 0.056. CONCLUSIONS:3D prostate cancer models derived from mpMRI data provide novel guidance for planning confluent treatment volumes for cPGA and predicted a greater number of treatment probes than traditional 2D planning methods. This study prompts further investigation into the use of 3D treatment planning techniques as the increase of partial gland ablation treatment protocols develop.