Browsing by Author "Virginia Tech Carilion School of Medicine"

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    The adhesion function of the sodium channel beta subunit (beta 1) contributes to cardiac action potential propagation
    Veeraraghavan, Rengasayee; Hoeker, Gregory S.; Alvarez-Laviada, Anita; Hoagland, Daniel T.; Wan, Xiaoping; King, D. Ryan; Sanchez-Alonso, Jose; Chen, Chunling; Jourdan, L. Jane; Isom, Lori L.; Deschenes, Isabelle; Smith, James W.; Gorelik, Julia; Poelzing, Steven; Gourdie, Robert G. (2018-08-14)
    Computational modeling indicates that cardiac conduction may involve ephaptic coupling - intercellular communication involving electrochemical signaling across narrow extracellular clefts between cardiomyocytes. We hypothesized that beta 1(SCN1B) - mediated adhesion scaffolds trans-activating Na(V)1.5 (SCN5A) channels within narrow (<30 nm) perinexal clefts adjacent to gap junctions (GJs), facilitating ephaptic coupling. Super-resolution imaging indicated preferential beta 1 localization at the perinexus, where it co-locates with Na(V)1.5. Smart patch clamp (SPC) indicated greater sodium current density (I-Na) at perinexi, relative to non-junctional sites. A novel, rationally designed peptide, beta adp1, potently and selectively inhibited beta 1-mediated adhesion, in electric cell-substrate impedance sensing studies. beta adp1 significantly widened perinexi in guinea pig ventricles, and selectively reduced perinexal I-Na, but not whole cell I-Na, in myocyte monolayers. In optical mapping studies, beta adp1 precipitated arrhythmogenic conduction slowing. In summary, beta 1-mediated adhesion at the perinexus facilitates action potential propagation between cardiomyocytes, and may represent a novel target for anti-arrhythmic therapies.
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    Assessment of a Continuing Medical Education Intervention Designed to Change Physician Practice Regarding Blood Transfusion
    Arulraja, Evangeline; Whicker, Shari A.; Shaver, Katherine; Wells, Linda; Dallas, A. Paul; Musick, David W. (2020-04-17)
    Background and Objectives: Excessive packed red blood cell (pRBC) transfusions are associated with worse clinical outcomes and unnecessary costs. While multi-faceted continuing medical education (CME) approaches have been shown to be effective methods for changing physician practice, few studies have evaluated this approach as a method for changing blood transfusion practices. Methods: In this prospective cohort study sought to use a multi-faceted CME platform to modify physician transfusion practices. In this prospective cohort study, the authors implemented a multi-faceted CME intervention including didactic presentations, distribution of educational materials, educational posters, and electronic medical record clinical decision support. Primary outcomes were number of pRBC transfusions prior to and after intervention and associated costs. Secondary outcomes included knowledge acquisition, satisfaction, self-reported improvement in knowledge, and intent to change behavior. The intervention targeted physicians from four departments: Surgery, Internal Medicine, Obstetrics and Gynecology, and Emergency Medicine. Results: Fifty-eight physicians participated in the experimental group and seventy-three physicians in the control group. There was a 26% decrease (P<.0001) in pRBC transfusions monthly when comparing the year prior to intervention to post-intervention year. Clinicians reported improved knowledge acquisition regarding transfusion risks and indications (P<.001). Adjusted transfusion practices saved the primary teaching hospital $722,950 following the intervention. Conclusion: This study supports the use of a multi-faceted CME intervention to align clinical practice with evidencebased transfusion guidelines. Future studies should investigate the effectiveness of individual components of multi-faceted CME interventions regarding improved physician knowledge and clinical practice, patient outcomes, and cost-benefit.
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    Association between PEG3 DNA methylation and high-grade cervical intraepithelial neoplasia
    Bosire, Claire; Vidal, Adriana C.; Smith, Jennifer S.; Jima, Dereje; Huang, Zhiqing; Skaar, David; Valea, Fidel; Bentley, Rex; Gradison, Margaret; Yarnall, Kimberly S. H.; Ford, Anne; Overcash, Francine; Murphy, Susan K.; Hoyo, Cathrine (2021-06-13)
    Background Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited. Methods Women (n = 419) were enrolled at colposcopic evaluation at Duke Medical Center in Durham, North Carolina. Human papillomavirus (HPV) was genotyped by HPV linear array and CIN grade was ascertained by biopsy pathologic review. DNA methylation was measured at differentially methylated regions (DMRs) regulating genomic imprinting of the IGF2/H19, IGF2AS, MESTIT1/MEST, MEG3, PLAGL1/HYMAI, KvDMR and PEG10, PEG3 imprinted domains, using Sequenom-EpiTYPER assays. Logistic regression models were used to evaluate the associations between HPV infection, DMR methylation and CIN risk overall and by race. Results Of the 419 participants, 20 had CIN3+, 52 had CIN2, and 347 had ≤ CIN1 (CIN1 and negative histology). The median participant age was 28.6 (IQR:11.6) and 40% were African American. Overall, we found no statistically significant association between altered methylation in selected DMRs and CIN2+ compared to ≤CIN1. Similarly, there was no significant association between DMR methylation and CIN3+ compared to ≤CIN2. Restricting the outcome to CIN2+ cases that were HR-HPV positive and p16 staining positive, we found a significant association with PEG3 DMR methylation (OR: 1.56 95% CI: 1.03–2.36). Conclusions While the small number of high-grade CIN cases limit inferences, our findings suggest an association between altered DNA methylation at regulatory regions of PEG3 and high grade CIN in high-risk HPV positive cases.
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    Building Health Systems Science Education from the Core Domain of Interprofessional Education at Virginia Tech Carilion School of Medicine
    Musick, David W.; Vari, Richard; Kraemer, M. Suzanne; Trinkle, David B.; Vari, Patty M.; Smith, Judy C.; Learman, Lee A. (2020-11-23)
    The Virginia Tech Carilion School of Medicine (VTCSOM) is a 4-year allopathic medical school in Roanoke, VA. The curriculum is organized into four learning domains: basic science, clinical science, research, and interprofessionalism (IPE). A recent curriculum renewal effort allowed the school to embark upon a redesign of the IPE learning domain to incorporate new core content from health systems science (HSS).We describe how our unique approach to IPE is being preserved as we innovate to produce graduates who are future thought leaders and “systems citizens,” prepared to deliver patient care with an expanded knowledge of the health systems in which they will eventually practice.
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    Burkitt-type lymphoma incidentally found as the cause of acute appendicitis: a case report and review of literature
    Shahmanyan, Davit; Saway, Brian F.; Palmerton, Hannah; Rudderow, John S.; Reed, Christopher M.; Wattsman, Terri-Ann; Faulks, Emily R.; Collier, Bryan R.; Budin, Robert E.; Hamill, Mark E. (2021-09-24)
    Background Appendectomy remains one of the most common emergency operations. Recent research supports the treatment of uncomplicated appendicitis with antibiotics alone. While nonoperative management of appendicitis may be safe in some patients, it may result in missed neoplasms. We present a case of acute appendicitis where the final pathology resulted in a diagnosis of a Burkitt-type lymphoma. Case presentation An 18-year-old male presented to the emergency department with 24 h of right lower quadrant pain with associated urinary retention, anorexia, and malaise. Past medical history was significant for intermittent diarrhea and anal fissure. He exhibited focal right lower quadrant tenderness. Workup revealed leukocytosis and CT uncovered acute appendicitis with periappendiceal abscess and no appendicolith. Laparoscopic appendectomy was performed and found acute appendicitis with associated abscess abutting the rectum and bladder. Pathology of the resected appendix reported acute appendicitis with evidence of Burkitt-type lymphoma. A PET scan did not reveal any residual disease. Hematology/oncology was consulted and chemotherapy was initiated with an excellent response. Conclusions Appendiceal lymphomas constitute less than 0.1% of gastrointestinal lymphomas. Primary appendix neoplasms are found in 0.5–1.0% of appendectomy specimens following acute appendicitis. In this case, appendectomy allowed for prompt identification and treatment of an aggressive, rapidly fatal lymphoma resulting in complete remission.
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    Characterization of Ablation Thresholds for 3D-Cultured Patient-Derived Glioma Stem Cells in Response to High-Frequency Irreversible Electroporation
    Ivey, J. W.; Wasson, E. M.; Alinezhadbalalami, N.; Kanitkar, A.; Debinski, Waldemar; Sheng, Z.; Davalos, Rafael V.; Verbridge, Scott S. (American Association for the Advancement of Science, 2019-04-28)
    High-frequency irreversible electroporation (H-FIRE) is a technique that uses pulsed electric fields that have been shown to ablate malignant cells. In order to evaluate the clinical potential of H-FIRE to treat glioblastoma (GBM), a primary brain tumor, we have studied the effects of high-frequency waveforms on therapy-resistant glioma stem-like cell (GSC) populations. We demonstrate that patient-derived GSCs are more susceptible to H-FIRE damage than primary normal astrocytes. This selectivity presents an opportunity for a degree of malignant cell targeting as bulk tumor cells and tumor stem cells are seen to exhibit similar lethal electric field thresholds, significantly lower than that of healthy astrocytes. However, neural stem cell (NSC) populations also exhibit a similar sensitivity to these pulses. This observation may suggest that different considerations be taken when applying these therapies in younger versus older patients, where the importance of preserving NSC populations may impose different restrictions on use.We also demonstrate variability in threshold among the three patient-derived GSC lines studied, suggesting the need for personalized cell-specific characterization in the development of potential clinical procedures. Future work may provide further useful insights regarding this patient-dependent variability observed that could inform targeted and personalized treatment.
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    The Clinical Impact of Fracture Liaison Services: A Systematic Review
    Barton, David W.; Piple, Amit S.; Smith, C. Taylor; Moskal, Sterling A.; Carmouche, Jonathan J. (2021-01-09)
    Introduction: A fracture liaison service (FLS) is a coordinated system of care that streamlines osteoporosis management in the orthopaedic setting and can serve as an effective form of secondary preventative care in these patients. The present work reviews the available evidence regarding the impact of fracture liaison services on clinical outcomes. Methods: The literature was reviewed for studies reporting changes in the rates of bone mineral density scanning (DXA), antiresorptive therapy, new minimum trauma fractures, and mortality between cohorts with access to an FLS or not. Studies including intention to treat level data were retained. A Medline search for "fracture liaison" OR "secondary fracture prevention" produced 146 results, 98 were excluded based on the abstract, 38 were excluded based on full-text review. Ten level III studies encompassing 48,045 patients were included, of which 5 studies encompassing 7,086 were analyzed. Odds-ratios for DXA and anti-osteoporosis pharmacotherapy rates were calculated from data. Fixed and random effects analyses were performed using the Mantel-Haenszel method. Results: Four studies reported, on average, a 6-fold improvement in DXA scanning rates (Figure 1). Six studies reported, on average, a 3-fold improvement in antiresorptive therapy rates (Figure 2). Four large studies reported significant reductions in the rate of new fractures using time-dependent Cox proportional hazards models at 12 months (HR = 0.84, 0.95), 24 months (HR = 0.44, 0.65), and 36 months (HR = 0.67). Five large studies reported mortality improvements using time-dependent Cox proportional hazards models at 12 months (HR = 0.88, 0.84, 0.81) and 24 months (HR = 0.65, 0.67). Conclusions: The findings suggest that fracture liaison services improve rates of DXA scanning and antiresorptive therapy as well as reductions in the rates of new fractures and mortality among patients seen following minimum trauma fractures across many time points.
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    Comparison of Amino Acid PET to Advanced and Emerging MRI Techniques for Neurooncology Imaging: A Systematic Review of the Recent Studies
    Stopa, Brittany M.; Juhász, Csaba; Mittal, Sandeep (Hindawi, 2021-01-20)
    Introduction. Standard neuroimaging protocols for brain tumors have well-known limitations. The clinical use of additional modalities including amino acid PET (aaPET) and advanced MRI (aMRI) techniques (including DWI, PWI, and MRS) is emerging in response to the need for more accurate detection of brain tumors. In this systematic review of the past 2 years of the literature, we discuss the most recent studies that directly compare or combine aaPET and aMRI for brain tumor imaging. Methods. A PubMed search was conducted for human studies incorporating both aaPET and aMRI and published between July 2018 and August 2020. Results. A total of 22 studies were found in the study period. Recent studies of aaPET with DWI showed a superiority of MET, FET, FDOPA, and AMT PET for detecting tumor, predicting recurrence, diagnosing progression, and predicting survival. Combining modalities further improved performance. Comparisons of aaPET with PWI showed mixed results about spatial correlation. However, both modalities were able to detect high-grade tumors, identify tumor recurrence, differentiate recurrence from treatment effects, and predict survival. aaPET performed better on these measures than PWI, but when combined, they had the strongest results. Studies of aaPET with MRS demonstrated that both modalities have diagnostic potential but MET PET and FDOPA PET performed better than MRS. MRS suffered from some data quality issues that limited analysis in two studies, and, in one study that combined modalities, overall performance actually decreased. Four recent studies compared aaPET with emerging MRI approaches (such as CEST imaging, MR fingerprinting, and SISTINA), but the initial results remain inconclusive. Conclusions. aaPET outperformed the aMRI imaging techniques in most recent studies. DWI and PWI added meaningful complementary data, and the combination of aaPET with aMRI yielded the best results in most studies.
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    Complete Genome Sequence of Pseudomonas aeruginosa CMC-115, a Clinical Strain from an Acute Ventilator-Associated Pneumonia Patient
    Adenikinju, Adenike; Jensen, Roderick V.; Kerkering, Thomas M.; Garner, Dorothy C.; Rao, Jayasimha (2020-07)
    We report the complete genome of clinical strain Pseudomonas aeruginosa CMC-115, which was isolated from an acute ventilator-associated pneumonia patient. Illumina sequencing reads were assembled using Geneious to yield a 6,375,262-bp circular chromosome that exhibited an unusual ferrichrome receptor in the pyoverdine synthesis locus and the absence of type 3 secretion system genes.
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    The conduction velocity-potassium relationship in the heart is modulated by sodium and calcium
    King, D. Ryan; Entz, Michael, II; Blair, Grace A.; Crandell, Ian; Hanlon, Alexandra L.; Lin, Joyce; Hoeker, Gregory S.; Poelzing, Steven (2021-03)
    The relationship between cardiac conduction velocity (CV) and extracellular potassium (K+) is biphasic, with modest hyperkalemia increasing CV and severe hyperkalemia slowing CV. Recent studies from our group suggest that elevating extracellular sodium (Na+) and calcium (Ca2+) can enhance CV by an extracellular pathway parallel to gap junctional coupling (GJC) called ephaptic coupling that can occur in the gap junction adjacent perinexus. However, it remains unknown whether these same interventions modulate CV as a function of K+. We hypothesize that Na+, Ca2+, and GJC can attenuate conduction slowing consequent to severe hyperkalemia. Elevating Ca2+ from 1.25 to 2.00 mM significantly narrowed perinexal width measured by transmission electron microscopy. Optically mapped, Langendorff-perfused guinea pig hearts perfused with increasing K+ revealed the expected biphasic CV-K+ relationship during perfusion with different Na+ and Ca2+ concentrations. Neither elevating Na+ nor Ca2+ alone consistently modulated the positive slope of CV-K+ or conduction slowing at 10-mM K+; however, combined Na+ and Ca2+ elevation significantly mitigated conduction slowing at 10-mM K+. Pharmacologic GJC inhibition with 30-mu M carbenoxolone slowed CV without changing the shape of CV-K+ curves. A computational model of CV predicted that elevating Na+ and narrowing clefts between myocytes, as occur with perinexal narrowing, reduces the positive and negative slopes of the CV-K+ relationship but do not support a primary role of GJC or sodium channel conductance. These data demonstrate that combinatorial effects of Na+ and Ca2+ differentially modulate conduction during hyperkalemia, and enhancing determinants of ephaptic coupling may attenuate conduction changes in a variety of physiologic conditions.
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    Connexin 43 peptidic medicine for glioblastoma stem cells
    Sheng, Zhi (Elsevier, 2021-02-01)
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    Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development
    Ates, Kristin M.; Wang, Tong; Moreland, Trevor; Veeranan-Karmegam, Rajalakshmi; Ma, Manxiu; Jeter, Chelsi; Anand, Priya; Wenzel, Wolfgang; Kim, Hyung-Goo; Wolfe, Lynne A.; Stephen, Joshi; Adams, David R.; Markello, Thomas; Tifft, Cynthia J.; Settlage, Robert E.; Gahl, William A.; Gonsalvez, Graydon B.; Malicdan, May Christine; Flanagan-Steet, Heather; Pan, Yuchin Albert (2020-05)
    A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain-containing endocytic trafficking adaptor 1 and 2 (PHETA1/2; also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here, we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, phetal and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentation of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient. This article has an associated First Person interview with the first author of the paper.
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    Demographic Trends in Paddle Lead Spinal Cord Stimulator Placement: Private Insurance and Medicare Beneficiaries
    Labaran, Lawal; Bell, Joshua; Puvanesarajah, Varun; Jain, Nikhil; Aryee, Jomar N. A.; Raad, Michael; Jain, Amit; Carmouche, Jonathan J.; Hassanzadeh, Hamid (2020-06)
    Objective: Although spinal cord stimulators (SCS) continue to gain acceptance as a viable nonpharmacologic option for the treatment of chronic back pain, recent trends are not well established. The aim of this study was to evaluate recent overall demographic and regional trends in paddle lead SCS placement and to determine if differences in trends exist between private-payer and Medicare beneficiaries. Methods: A retrospective review of Medicare and private-payer insurance records from 2007-2014 was performed to identify patients who underwent a primary paddle lead SCS placement via a laminectomy (CPT-63655). Each study cohort was queried to determine the annual rate of SCS placements and demographic characteristics. Yearly SCS implantation rates within the study cohorts were adjusted per 100,000 beneficiaries. A chi-square analysis was used to compare changes in annual rates. Results: A total of 31,352 Medicare and 2,935 private-payer patients were identified from 2007 to 2014. Paddle lead SCS placements ranged from 5.9 to 17.5 (p<0.001), 1.9 to 5.9 (p<0.001), and 5.2 to 14.5 (p<0.001) placements per 100,000 Medicare, private-payer, and overall beneficiaries respectively from 2007 to 2014. SCS placements peaked in 2013 with 19.6, 7.1, and 16.8 placements per 100,000 Medicare, private-payer, and overall patients. Conclusion: There was an overall increase in the annual rate of SCS placements from 2007 to 2014. Paddle lead SCS placements peaked in 2013 for Medicare, private-payer, and overall beneficiaries. The highest incidence of implantation was in the Southern region of the United States and among females. Yearly adjusted rates of SCSs were higher among Medicare patients at all time points.
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    Development and implementation of a scalable and versatile test for COVID-19 diagnostics in rural communities
    Ceci, Alessandro; Muñoz-Ballester, Carmen; Tegge, Allison N.; Brown, Katherine L.; Umans, Robyn A.; Michel, F. Marc; Patel, Dipankumar; Tewari, Bhanu P.; Martin, James E.; Alcoreza, Oscar Jr.; Maynard, Thomas M.; Martinez-Martinez, Daniel; Bordwine, Paige; Bissell, Noelle; Friedlander, Michael J.; Sontheimer, Harald; Finkielstein, Carla V. (Nature Publishing Group, 2021-07-20)
    Rapid and widespread testing of severe acute respiratory coronavirus 2 (SARS-CoV-2) is essential for an effective public health response aimed at containing and mitigating the coronavirus disease 2019 (COVID-19) pandemic. Successful health policy implementation relies on early identification of infected individuals and extensive contact tracing. However, rural communities, where resources for testing are sparse or simply absent, face distinctive challenges to achieving this success. Accordingly, we report the development of an academic, public land grant University laboratory-based detection assay for the identification of SARS-CoV-2 in samples from various clinical specimens that can be readily deployed in areas where access to testing is limited. The test, which is a quantitative reverse transcription polymerase chain reaction (RT-qPCR)-based procedure, was validated on samples provided by the state laboratory and submitted for FDA Emergency Use Authorization. Our test exhibits comparable sensitivity and exceeds specificity and inclusivity values compared to other molecular assays. Additionally, this test can be re-configured to meet supply chain shortages, modified for scale up demands, and is amenable to several clinical specimens. Test development also involved 3D engineering critical supplies and formulating a stable collection media that allowed samples to be transported for hours over a dispersed rural region without the need for a cold-chain. These two elements that were critical when shortages impacted testing and when personnel needed to reach areas that were geographically isolated from the testing center. Overall, using a robust, easy-to-adapt methodology, we show that an academic laboratory can supplement COVID-19 testing needs and help local health departments assess and manage outbreaks. This additional testing capacity is particularly germane for smaller cities and rural regions that would otherwise be unable to meet the testing demand.
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    Development of endometrial stromal sarcoma in a patient undergoing in vitro fertilization: A case report
    Patel, Tulsi; Sosa-Stanley, Jessica N.; Evans-Hoeker, Emily; Osborne, Janet L. (2020-05)
    Development of endometrial stromal sarcoma during in vitro fertilization (IVF) is rare. We encountered a case of endometrial stromal sarcoma (ESS) presenting as a new endometrial mass in a patient undergoing donor egg IVF, despite normal imaging and exams prior to and throughout treatment. To our knowledge, this is the only report describing the rapid growth of ESS during IVF treatment. When diagnosing an endometrial stromal sarcoma, it is important for the clinician and patient to be aware that full histologic inspection is required to distinguish it from a benign neoplasm. Given the need for a hysterectomy for definitive diagnosis, this case presents ethical challenges and potential for patient distress.
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    Direct Common Carotid Artery Puncture for Endovascular Treatment of Acute Large Vessel Ischemic Stroke in a Patient With Congenital Rare Variant of the Great Vessels
    Plant, Samuel; Patel, Biraj M. (2020-10-24)
    This report describes a case of acute left middle cerebral artery ischemic stroke that occurred in a patient with unique anatomy of the vessels arising from the aortic arch that remained undiagnosed until the age of 36. The nature of the anatomical variance proved problematic in establishing access to the carotid artery via traditional transfemoral or transbrachial approaches, and direct access was established via left carotid puncture. The patient regained substantial neurologic function. The direct carotid approach described below serves as a viable alternate route to establishing reperfusion in patients with complex or problematic aortic arch anatomy.
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    Diverse GABAergic neurons organize into subtype-specific sublaminae in the ventral lateral geniculate nucleus
    Sabbagh, Ubadah; Govindaiah, Gubbi; Somaiya, Rachana D.; Ha, Ryan V.; Wei, Jessica C.; Guido, William; Fox, Michael A. (Wiley, 2020-05-19)
    In the visual system, retinal axons convey visual information from the outside world to dozens of distinct retinorecipient brain regions and organize that information at several levels, including either at the level of retinal afferents, cytoarchitecture of intrinsic retinorecipient neurons, or a combination of the two. Two major retinorecipient nuclei which are densely innervated by retinal axons are the dorsal lateral geniculate nucleus, which is important for classical image-forming vision, and ventral LGN (vLGN), which is associated with non-image-forming vision. The neurochemistry, cytoarchitecture, and retinothalamic connectivity in vLGN remain unresolved, raising fundamental questions of how it receives and processes visual information. To shed light on these important questions, used in situ hybridization, immunohistochemistry, and genetic reporter lines to identify and characterize novel neuronal cell types in mouse vLGN. Not only were a high percentage of these cells GABAergic, we discovered transcriptomically distinct GABAergic cell types reside in the two major laminae of vLGN, the retinorecipient, external vLGN (vLGNe) and the non-retinorecipient, internal vLGN (vLGNi). Furthermore, within vLGNe, we identified transcriptionally distinct subtypes of GABAergic cells that are distributed into four adjacent sublaminae. Using trans-synaptic viral tracing and in vitro electrophysiology, we found cells in each these vLGNe sublaminae receive monosynaptic inputs from retina. These results not only identify novel subtypes of GABAergic cells in vLGN, they suggest the subtype-specific laminar distribution of retinorecipient cells in vLGNe may be important for receiving, processing, and transmitting light-derived signals in parallel channels of the subcortical visual system.
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    Dysregulation of Ambient Glutamate and Glutamate Receptors in Epilepsy: An Astrocytic Perspective
    Alcoreza, Oscar Jr.; Patel, Dipan C.; Tewari, Bhanu P.; Sontheimer, Harald (2021-03-22)
    Given the important functions that glutamate serves in excitatory neurotransmission, understanding the regulation of glutamate in physiological and pathological states is critical to devising novel therapies to treat epilepsy. Exclusive expression of pyruvate carboxylase and glutamine synthetase in astrocytes positions astrocytes as essential regulators of glutamate in the central nervous system (CNS). Additionally, astrocytes can significantly alter the volume of the extracellular space (ECS) in the CNS due to their expression of the bi-directional water channel, aquaporin-4, which are enriched at perivascular endfeet. Rapid ECS shrinkage has been observed following epileptiform activity and can inherently concentrate ions and neurotransmitters including glutamate. This review highlights our emerging knowledge on the various potential contributions of astrocytes to epilepsy, particularly supporting the notion that astrocytes may be involved in seizure initiation via failure of homeostatic responses that lead to increased ambient glutamate. We also review the mechanisms whereby ambient glutamate can influence neuronal excitability, including via generation of the glutamate receptor subunit GluN2B-mediated slow inward currents, as well as indirectly affect neuronal excitability via actions on metabotropic glutamate receptors that can potentiate GluN2B currents and influence neuronal glutamate release probabilities. Additionally, we discuss evidence for upregulation of System xc-, a cystine/glutamate antiporter expressed on astrocytes, in epileptic tissue and changes in expression patterns of glutamate receptors.
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    EGR1 recruits TET1 to shape the brain methylome during development and upon neuronal activity
    Sun, Zhixiong; Xu, Xiguang; He, Jianlin; Murray, Alexander; Sun, Ming-an; Wei, Xiaoran; Wang, Xia; McCoig, Emmarose; Xie, Evan; Jiang, Xi; Li, Liwu; Zhu, Jinsong; Chen, Jianjun; Morozov, Alexei; Pickrell, Alicia M.; Theus, Michelle H.; Xie, Hehuang David (2019-08-29)
    Life experience can leave lasting marks, such as epigenetic changes, in the brain. How life experience is translated into storable epigenetic information remains largely unknown. With unbiased data-driven approaches, we predicted that Egr1, a transcription factor important for memory formation, plays an essential role in brain epigenetic programming. We performed EGR1 ChIP-seq and validated thousands of EGR1 binding sites with methylation patterns established during postnatal brain development. More specifically, these EGR1 binding sites become hypomethylated in mature neurons but remain heavily methylated in glia. We further demonstrated that EGR1 recruits a DNA demethylase TET1 to remove the methylation marks and activate downstream genes. The frontal cortices from the knockout mice lacking Egr1 or Tet1 share strikingly similar profiles in both gene expression and DNA methylation. In summary, our study reveals EGR1 programs the brain methylome together with TET1 providing new insight into how life experience may shape the brain methylome.