Scopus list of publications for November 20, 2022
An allosteric modulator activates BK channels by perturbing coupling between Ca2+ binding and pore opening
(2022) Nature Communications, 13 (1), art. no. 6784, .
Zhang, G.a , Xu, X.b c d e , Jia, Z.f g , Geng, Y.h , Liang, H.a , Shi, J.a , Marras, M.a , Abella, C.a , Magleby, K.L.h , Silva, J.R.a , Chen, J.f g , Zou, X.b c d e , Cui, J.a
a Department of Biomedical Engineering, Center for the Investigation of Membrane Excitability Disorders, Cardiac Bioelectricity and Arrhythmia Center, Washington University, St. Louis, MO, United States
b Dalton Cardiovascular Research Center, University of Missouri – Columbia, Columbia, MO, United States
c Department of Physics and Astronomy, University of Missouri – Columbia, Columbia, MO, United States
d Department of Biochemistry, University of Missouri – Columbia, Columbia, MO, United States
e Institute for Data Science and Informatics, University of Missouri – Columbia, Columbia, MO, United States
f Department of Chemistry, University of Massachusetts, Amherst, MA, United States
g Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA, United States
h Department of Physiology and Biophysics, University of Miami Miller School of Medicine, Miami, FL, United States
Abstract
BK type Ca2+-activated K+ channels activate in response to both voltage and Ca2+. The membrane-spanning voltage sensor domain (VSD) activation and Ca2+ binding to the cytosolic tail domain (CTD) open the pore across the membrane, but the mechanisms that couple VSD activation and Ca2+ binding to pore opening are not clear. Here we show that a compound, BC5, identified from in silico screening, interacts with the CTD-VSD interface and specifically modulates the Ca2+ dependent activation mechanism. BC5 activates the channel in the absence of Ca2+ binding but Ca2+ binding inhibits BC5 effects. Thus, BC5 perturbs a pathway that couples Ca2+ binding to pore opening to allosterically affect both, which is further supported by atomistic simulations and mutagenesis. The results suggest that the CTD-VSD interaction makes a major contribution to the mechanism of Ca2+ dependent activation and is an important site for allosteric agonists to modulate BK channel activation. © 2022, The Author(s).
Funding details
National Institutes of HealthNIH
Document Type: Article
Publication Stage: Final
Source: Scopus
Neoadjuvant stereotactic radiosurgery for brain metastases: a new paradigm
(2022) Neurosurgical Focus, 53 (5), art. no. E8, .
Li, Y.D.a , Coxon, A.T.a , Huang, J.b d , Abraham, C.D.b d , Dowling, J.L.a b d , Leuthardt, E.C.a b d , Dunn, G.P.c , Kim, A.H.a b d , Dacey, R.G.a b d , Zipfel, G.J.a b d , Evans, J.a , Filiput, E.A.a b , Chicoine, M.R.a b d e
a Department of Neurosurgery, Washington University School of Medicine, St. Louis, United States
b Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, United States
c Department of Neurosurgery, Harvard Medical School, Boston, MA, United States
d The Brain Tumor Center, Siteman Cancer Center, Washington University School of Medicine, St. Louis, United States
e Department of Neurosurgery, University of Missouri, Columbia, MO, United States
Abstract
OBJECTIVE For patients with surgically accessible solitary metastases or oligometastatic disease, treatment often involves resection followed by postoperative stereotactic radiosurgery (SRS). This strategy has several potential drawbacks, including irregular target delineation for SRS and potential tumor “seeding” away from the resection cavity during surgery. A neoadjuvant (preoperative) approach to radiation therapy avoids these limitations and offers improved patient convenience. This study assessed the efficacy of neoadjuvant SRS as a new treatment paradigm for patients with brain metastases. METHODS A retrospective review was performed at a single institution to identify patients who had undergone neoadjuvant SRS (specifically, Gamma Knife radiosurgery) followed by resection of a brain metastasis. Kaplan-Meier survival and log-rank analyses were used to evaluate risks of progression and death. Assessments were made of local recurrence and leptomeningeal spread. Additionally, an analysis of the contemporary literature of postoperative and neoadjuvant SRS for metastatic disease was performed. RESULTS Twenty-four patients who had undergone neoadjuvant SRS followed by resection of a brain metastasis were identified in the single-institution cohort. The median age was 64 years (range 32–84 years), and the median follow-up time was 16.5 months (range 1 month to 5.7 years). The median radiation dose was 17 Gy prescribed to the 50% isodose. Rates of local disease control were 100% at 6 months, 87.6% at 12 months, and 73.5% at 24 months. In 4 patients who had local treatment failure, salvage therapy included repeat resection, laser interstitial thermal therapy, or repeat SRS. One hundred thirty patients (including the current cohort) were identified in the literature who had been treated with neoadjuvant SRS prior to resection. Overall rates of local control at 1 year after neoadjuvant SRS treatment ranged from 49% to 91%, and rates of leptomeningeal dissemination from 0% to 16%. In comparison, rates of local control 1 year after postoperative SRS ranged from 27% to 91%, with 7% to 28% developing leptomeningeal disease. CONCLUSIONS Neoadjuvant SRS for the treatment of brain metastases is a novel approach that mitigates the shortcomings of postoperative SRS. While additional prospective studies are needed, the current study of 130 patients including the summary of 106 previously published cases supports the safety and potential efficacy of preoperative SRS with potential for improved outcomes compared with postoperative SRS. © AANS 2022, except where prohibited by US copyright law
Author Keywords
Brain metastasis; Neoadjuvant stereotactic radiosurgery; Preoperative; Resection
Funding details
National Cancer InstituteNCIP30 CA091842
National Institute of Neurological Disorders and StrokeNINDS
Alvin J. Siteman Cancer Center
Head for the Cure FoundationHFTC
Document Type: Article
Publication Stage: Final
Source: Scopus
Reconstructing neural circuits using multiresolution correlated light and electron microscopy
(2022) Frontiers in Neural Circuits, 16, art. no. 753496, .
Friedrichsen, K.a b c , Ramakrishna, P.a b c , Hsiang, J.-C.a b c , Valkova, K.a b c , Kerschensteiner, D.a b c , Morgan, J.L.a b c
a Department of Ophthalmology and Visual Sciences, Washington University in St. Louis, St. LouisMO, United States
b Department of Neuroscience, Washington University in St. Louis, St. LouisMO, United States
c Department of Biomedical Engineering, Washington University in St. Louis, St. LouisMO, United States
Abstract
Correlated light and electron microscopy (CLEM) can be used to combine functional and molecular characterizations of neurons with detailed anatomical maps of their synaptic organization. Here we describe a multiresolution approach to CLEM (mrCLEM) that efficiently targets electron microscopy (EM) imaging to optically characterized cells while maintaining optimal tissue preparation for high-throughput EM reconstruction. This approach hinges on the ease with which arrays of sections collected on a solid substrate can be repeatedly imaged at different scales using scanning electron microscopy. We match this multiresolution EM imaging with multiresolution confocal mapping of the aldehyde-fixed tissue. Features visible in lower resolution EM correspond well to features visible in densely labeled optical maps of fixed tissue. Iterative feature matching, starting with gross anatomical correspondences and ending with subcellular structure, can then be used to target high-resolution EM image acquisition and annotation to cells of interest. To demonstrate this technique and range of images used to link live optical imaging to EM reconstructions, we provide a walkthrough of a mouse retinal light to EM experiment as well as some examples from mouse brain slices. Copyright © 2022 Friedrichsen, Ramakrishna, Hsiang, Valkova, Kerschensteiner and Morgan.
Author Keywords
confocal 3D microscopy; connectomics; correlated light and electron microscopy (CLEM); electron microscopy; neural circuit; synapse; tissue mapping
Funding details
National Institutes of HealthNIHEY023341, EY026978, EY027411, EY029313, EYE030623
Research to Prevent BlindnessRPB
Document Type: Article
Publication Stage: Final
Source: Scopus
Vascular endothelial-cadherin as a marker of endothelial injury in preclinical Alzheimer disease
(2022) Annals of Clinical and Translational Neurology, .
Tarawneh, R.a b , Kasper, R.S.a , Sanford, J.c d , Phuah, C.-L.d e , Hassenstab, J.f , Cruchaga, C.c d
a Department of Neurology, University of New Mexico, Albuquerque, NM, United States
b Center for Memory and Aging, University of New Mexico, Albuquerque, NM, United States
c Department of Psychiatry, Washington University in St Louis, St. Louis, MO, United States
d NeuroGenomics and Informatics Center, Washington University in St LouisMO, United States
e Department of Neurology, Washington University in St Louis, St. Louis, MO, United States
f Department of Psychology, Washington University in St Louis, St. Louis, MO, United States
Abstract
Objective: Endothelial dysfunction is an early and prevalent pathology in Alzheimer disease (AD). We here investigate the value of vascular endothelial-cadherin (VEC) as a cerebrospinal fluid (CSF) marker of endothelial injury in preclinical AD. Methods: Cognitively normal participants (Clinical Dementia Rating [CDR] 0) from the Knight Washington University-ADRC were included in this study (n = 700). Preclinical Alzheimer’s Cognitive Composite (PACC) scores, CSF VEC, tau, p-tau181, Aβ42/Aβ40, neurofilament light-chain (NFL) levels, and magnetic resonance imaging (MRI) assessments of white matter injury (WMI) were obtained from all participants. A subset of participants underwent brain amyloid imaging using positron emission tomography (amyloid-PET) (n = 534). Linear regression examined associations of CSF VEC with PACC and individual cognitive scores in preclinical AD. Mediation analyses examined whether CSF VEC mediated effects of CSF amyloid and tau markers on cognition in preclinical AD. Results: CSF VEC levels significantly correlated with PACC and individual cognitive scores in participants with amyloid (A+T±N±; n = 558) or those with amyloid and tau pathologies (A+T+N±; n = 259), after adjusting for covariates. CSF VEC also correlated with CSF measures of amyloid, tau, and neurodegeneration and global amyloid burden on amyloid-PET scans in our cohort. Importantly, our findings suggest that CSF VEC mediates associations of CSF Aβ42/Aβ40, p-tau181, and global amyloid burden with cognitive outcomes in preclinical AD. Interpretation: Our results support the utility of CSF VEC as a marker of endothelial injury in AD and highlight the importance of endothelial injury as an early pathology that contributes to cognitive impairment in even the earliest preclinical stages. © 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Funding details
P30NS048056
National Institutes of HealthNIHP20AG068077, R21AG067755‐01A1
National Institute on AgingNIA
National Institute of Neurological Disorders and StrokeNINDSK23 NS110927, P01AG03991, R01AG044546, RF1AG053303, RF1AG058501, U01AG058922
Foundation for Barnes-Jewish HospitalFBJH3962
Hope Center for Neurological Disorders
Chan Zuckerberg InitiativeCZIP01AG026276, P30AG066444, P50AG05681
Centene CorporationP19‐00559
Document Type: Article
Publication Stage: Article in Press
Source: Scopus
Associations of Stages of Objective Memory Impairment with Cerebrospinal Fluid and Neuroimaging Biomarkers of Alzheimer’s Disease
(2022) Journal of Prevention of Alzheimer’s Disease, .
Petersen, K.K.a , Ezzati, A.a , Lipton, R.B.a , Gordon, B.A.b , Hassenstab, J.b , Morris, J.C.b , Grober, E.a
a Saul R. Korey Department of Neurology, Albert Einstein College of Medicine, 1225 Morris Park Avenue, Bronx, NY 10461, United States
b Department of Neurology, Washington University School of Medicine, St. Louis, MO, United States
Abstract
Objective: To investigate cerebrospinal fluid (CSF) and neuroimaging correlates of Stages of Objective Memory Impairment (SOMI) based on Free and Cued Selective Reminding Test (FCSRT) performance, and to evaluate the effect of APOE ε4 status on this relationship. Methods: Data from 586 cognitively unimpaired individuals who had FCSRT, CSF, and volumetric magnetic resonance imaging (MRI) measures available was used. We compared CSF measures of β-amyloid (Aβ42/Aβ40 ratio), phosphorylated tau (p-Tau181), total tau (t-Tau), hippocampal volume, and PIB-PET mean cortical binding potential with partial volume correction (MCBP) among SOMI groups in the whole sample and in subsamples stratified by APOE ε4 status. Results: Participants had a mean age of 67.4 (SD=9.1) years, had 16.1 (SD=2.6) years of education, 57.0% were female, and 33.8% were APOE ε4 positive. In the entire sample, there was no significant difference between SOMI stages in Aβ42/Aβ40 ratio, p-Tau181, t-Tau, or PIB-PET MCBP when adjusted for age, sex, and education. However, higher SOMI stages had smaller hippocampal volume (F=3.29, p=0.020). In the stratified sample based on APOE ε4 status, in APOE ε4 positive individuals, higher SOMI stages had higher p-Tau181 (F=2.94, p=0.034) higher t-Tau (F=3.41, p=0.019), and smaller hippocampal volume (F=5.78, p<0.001). There were no significant differences in CSF or imaging biomarkers between SOMI groups in the APOE ε4 negative subsample. Conclusion: Cognitively normal older individuals with higher SOMI stages have higher in-vivo tau and neurodegenerative pathology only in APOE ε4 carriers. These original results indicate the potential usefulness of the SOMI staging system in assessing of tau and neurodegenerative pathology. © 2022, Serdi.
Author Keywords
APOE e4; biomarkers; cerebrospinal fluid; cognition; SOMI
Funding details
National Institutes of HealthNIH30 AG066444, P01 AG026276, P01AG003991, U19 AG024904, U19 AG032438
National Institute on AgingNIA2PO1 AG003949, K23 AG063993
Alzheimer’s AssociationAA2019-AACSF-641329
Document Type: Article
Publication Stage: Article in Press
Source: Scopus