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Recent Submissions
Editorial: Steroid receptors in neuron and glia
(Frontiers Media S.A., 2024-08-14) Le Menuet, Damien; Charalampopoulos, Ioannis N.; Cunningham, Rebecca L.; Kalafatakis, Konstantinos; Nalvarte, Ivan
Morphological variability in the inner ear of mice with osteogenesis imperfecta
(John Wiley & Sons, Inc., 2023-07-29) Huston, Lila A.; Husain, Tooba S.; Moore, Jacob C.; Organ, Jason M.; Menegaz, Rachel A.; Handler, Emma K.; Gonzales, Lauren A.
Osteogenesis imperfecta (OI) is known to cause hearing loss in ~60% of the affected human population. While OI-related pathologies have been studied in the middle ear, the development of cochlear pathologies is less well understood. In this study, we examine OI-related pathologies of the cochlea in a mouse model of OI to (1) document variation between OI and unaffected mice, and (2) assess the intrusion of the otic capsule onto the cochlea by analyzing differences in duct volumes. Juvenile and adult OIM C57BL/6mice were compared to unaffected wildtype (WT) mice using three-dimensional models of the cochlea generated from high resolution micro-CT scans. Two-tailed Mann-Whitney U tests were then used to investigate duct volume differences both within and between the OI and WT samples. Areas of higher ossification were observed at the cochlear base in the OI sample. OI mice also had significant intraindividual differences in duct volume between right and left ears (4%-15%), an effect not observed in WT mice. WT and OI duct volumes showed a large degree of overlap, although the OIM volumes were more variable. Our findings indicate that OIM mice are likely to exhibit more asymmetry and variation in cochlear volume despite minor differences in sample cochlear volumes, possibly due to bony capsule intrusion. This suggests a potential mechanism of hearing loss, and a high potential for cochlear and otic capsule alteration in OIM mice.
Tracking the burden, distribution, and impact of Post-COVID conditions in diverse populations for children, adolescents, and adults (Track PCC): passive and active surveillance protocols
(BioMed Central Ltd., 2024-08-29) Jones, Resa M.; Andrews, Jennifer G.; Dalton, Alexandra F.; Dixon, Brian E.; Dzomba, Bari J.; Fernando, Shane I.; Pogreba-Brown, Kristen M.; Ortiz, Miguel R.; Sharma, Vinita; Simmons, Nicole; Saydah, Sharon H.; Track, PCC Study Group
BACKGROUND: Track PCC includes five geographic surveillance sites to conduct standardized population-based surveillance to estimate and track Post-COVID Conditions (PCC) by age, sex, race/ethnicity, geographic area, severity of initial infection, and risk factors among persons with evidence of SARS-CoV-2 infection (based on the Council of State and Territorial Epidemiologist [CSTE] case definitions for confirmed cases or laboratory-confirmed evidence of infection). METHODS: The study will estimate the incidence, prevalence, including temporal trends, and duration and severity of PCC symptoms, among children, adolescents, and adults. PCCs include a broad range of symptoms and conditions that continue or develop after acute SARS-CoV-2 infection or COVID-19 illness. Surveillance includes both passive and active components for diverse populations in Arizona, Indiana, and Utah as well as the Bronx Borough, NY, and part of Philadelphia County, PA. Passive surveillance will utilize electronic health records and health information exchanges within each site catchment area to longitudinally follow persons with COVID-19 to estimate PCC occurring at least 30 days after acute COVID-19 illness. Active surveillance will utilize self-report of PCCs from detailed surveys of persons ages 7 years and older with evidence of SARS-CoV-2 infection in the past 3 months. Respondents will complete follow-up surveys at 6-, 12- and 18-months post-infection. DISCUSSION: These data can help identify which groups are most affected by PCC, and what health differences among demographic groups exist, as well as indicate potential barriers to care. These additional levels of granularity can inform public health action and help direct needed clinical care for patients.
SMRT Sequencing Enables High-Throughput Identification of Novel AAVs from Capsid Shuffling and Directed Evolution
(MDPI, 2023-08-21) Casy, Widler; Garza, Irvin T.; Chen, Xin; Dong, Thomas; Hu, Yuhui; Kanchwala, Mohammed; Trygg, Cynthia B.; Shyng, Charles; Xing, Chao; Bunnell, Bruce A.; Braun, Stephen E.; Gray, Steven J.
The use of AAV capsid libraries coupled with various selection strategies has proven to be a remarkable approach for generating novel AAVs with enhanced and desired features. The inability to reliably sequence the complete capsid gene in a high-throughput manner has been the bottleneck of capsid engineering. As a result, many library strategies are confined to localized and modest alterations in the capsid, such as peptide insertions or single variable region (VR) alterations. The caveat of short reads by means of next-generation sequencing (NGS) hinders the diversity of capsid library construction, shifting the field away from whole-capsid modifications. We generated AAV capsid shuffled libraries of naturally occurring AAVs and applied directed evolution in both mice and non-human primates (NHPs), with the goal of yielding AAVs that are compatible across both species for translational applications. We recovered DNA from the tissues of injected animal and used single molecule real-time (SMRT) sequencing to identify variants enriched in the central nervous system (CNS). We provide insights and considerations for variant identification by comparing bulk tissue sequencing to that of isolated nuclei. Our work highlights the potential advantages of whole-capsid engineering, as well as indispensable methodological improvements for the analysis of recovered capsids, including the nuclei-enrichment step and SMRT sequencing.
Discovery and Characterization of a Chemical Probe for Cyclin-Dependent Kinase-Like 2
(American Chemical Society, 2024-07-03) Bashore, Frances M.; Min, Sophia M.; Chen, Xiangrong; Howell, Stefanie; Rinderle, Caroline H.; Morel, Gabriel; Silvaroli, Josie A.; Wells, Carrow I.; Bunnell, Bruce A.; Drewry, David H.; Pabla, Navjot S.; Ultanir, Sila K.; Bullock, Alex N.; Axtman, Alison D.
Acylaminoindazole-based inhibitors of CDKL2 were identified via analyses of cell-free binding and selectivity data. Compound 9 was selected as a CDKL2 chemical probe based on its potent inhibition of CDKL2 enzymatic activity, engagement of CDKL2 in cells, and excellent kinome-wide selectivity, especially when used in cells. Compound 16 was designed as a negative control to be used alongside compound 9 in experiments to interrogate CDKL2-mediated biology. A solved cocrystal structure of compound 9 bound to CDKL2 highlighted key interactions it makes within its ATP-binding site. Inhibition of downstream phosphorylation of EB2, a CDKL2 substrate, in rat primary neurons provided evidence that engagement of CDKL2 by compound 9 in cells resulted in inhibition of its activity. When used at relevant concentrations, compound 9 does not impact the viability of rat primary neurons or certain breast cancer cells nor elicit consistent changes in the expression of proteins involved in epithelial-mesenchymal transition.