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1. A Rab-bit hole: Rab40 GTPases as new regulators of the actin cytoskeleton and cell migration

Author

Andrew J. Neumann and Rytis Prekeris

Subjects
Rab40 GTPases, SOCS box, ubiquitination, actin, cytoskeleton, cell migration, Biology (General), QH301-705.5
Abstract

The regulation of machinery involved in cell migration is vital to the maintenance of proper organism function. When migration is dysregulated, a variety of phenotypes ranging from developmental disorders to cancer metastasis can occur. One of the primary structures involved in cell migration is the actin cytoskeleton. Actin assembly and disassembly form a variety of dynamic structures which provide the pushing and contractile forces necessary for cells to properly migrate. As such, actin dynamics are tightly regulated. Classically, the Rho family of GTPases are considered the major regulators of the actin cytoskeleton during cell migration. Together, this family establishes polarity in the migrating cell by stimulating the formation of various actin structures in specific cellular locations. However, while the Rho GTPases are acknowledged as the core machinery regulating actin dynamics and cell migration, a variety of other proteins have become established as modulators of actin structures and cell migration. One such group of proteins is the Rab40 family of GTPases, an evolutionarily and functionally unique family of Rabs. Rab40 originated as a single protein in the bilaterians and, through multiple duplication events, expanded to a four-protein family in higher primates. Furthermore, unlike other members of the Rab family, Rab40 proteins contain a C-terminally located suppressor of cytokine signaling (SOCS) box domain. Through the SOCS box, Rab40 proteins interact with Cullin5 to form an E3 ubiquitin ligase complex. As a member of this complex, Rab40 ubiquitinates its effectors, controlling their degradation, localization, and activation. Because substrates of the Rab40/Cullin5 complex can play a role in regulating actin structures and cell migration, the Rab40 family of proteins has recently emerged as unique modulators of cell migration machinery.

Published
2023
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2. The molecular biology of tubulinopathies: Understanding the impact of variants on tubulin structure and microtubule regulation

Author

Katelyn J. Hoff, Andrew J. Neumann, and Jeffrey K. Moore

Subjects
tubulinopathy, microtubule, neurodevelopment, cytoskeleton, protein structure, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract

Heterozygous, missense mutations in both α- and β-tubulin genes have been linked to an array of neurodevelopment disorders, commonly referred to as “tubulinopathies.” To date, tubulinopathy mutations have been identified in three β-tubulin isotypes and one α-tubulin isotype. These mutations occur throughout the different genetic domains and protein structures of these tubulin isotypes, and the field is working to address how this molecular-level diversity results in different cellular and tissue-level pathologies. Studies from many groups have focused on elucidating the consequences of individual mutations; however, the field lacks comprehensive models for the molecular etiology of different types of tubulinopathies, presenting a major gap in diagnosis and treatment. This review highlights recent advances in understanding tubulin structural dynamics, the roles microtubule-associated proteins (MAPs) play in microtubule regulation, and how these are inextricably linked. We emphasize the value of investigating interactions between tubulin structures, microtubules, and MAPs to understand and predict the impact of tubulinopathy mutations at the cell and tissue levels. Microtubule regulation is multifaceted and provides a complex set of controls for generating a functional cytoskeleton at the right place and right time during neurodevelopment. Understanding how tubulinopathy mutations disrupt distinct subsets of those controls, and how that ultimately disrupts neurodevelopment, will be important for establishing mechanistic themes among tubulinopathies that may lead to insights in other neurodevelopment disorders and normal neurodevelopment.

Published
2022
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4. Risk of severe acute respiratory syndrome coronavirus 2 infection among women with polycystic ovary syndrome

Author

Snigdha Alur-Gupta, Mary Regina Boland, Anuja Dokras, Melissa A. Haendel, Christopher G. Chute, Anita Walden, Kenneth R. Gersing, Leonie Misquitta, Penny Wung Burgoon, Samuel Bozzette, Mariam Deacy, Christopher Dillon, Rebecca Erwin-Cohen, Nicole Garbarini, Valery Gordon, Michael G. Kurilla, Emily Carlson Marti, Sam G. Michael, Lili Portilla, Clare Schmitt, Meredith Temple-O'Connor, Tellen D. Bennett, David A. Eichmann, Justin Guinney, Warren A. Kibbe, Hongfang Liu, Philip R.O. Payne, Emily R. Pfaff, Peter N. Robinson, Joel H. Saltz, Heidi Spratt, Justin Starren, Christine Suver, Adam B. Wilcox, Andrew E. Williams, Chunlei Wu, Davera Gabriel, Stephanie S. Hong, Kristin Kostka, Harold P. Lehmann, Richard A. Moffitt, Michele Morris, Matvey B. Palchuk, Xiaohan Tanner Zhang, Richard L. Zhu, Marshall Clark, Andrew T. Girvin, Adam M. Lee, Robert T. Miller, Kellie M. Walters, Will Cooper, Patricia A. Francis, Rafael Fuentes, Alexis Graves, Julie A. McMurry, Andrew J. Neumann, Shawn T. O'Neil, Usman Sheikh, Elizabeth Zampino, Mark M. Bissell, Katie Rebecca Bradwell, Amin Manna, Nabeel Qureshi, Mary Morrison Saltz, Andréa M. Volz, Carolyn Bramante, Jeremy Richard Harper, Wenndy Hernandez, Farrukh M. Koraishy, Federico Mariona, Amit Saha, and Satyanarayana Vedula

Subjects
Reproductive Medicine, Obstetrics and Gynecology
Published
2023

5. Characteristics, Outcomes, and Severity Risk Factors Associated With SARS-CoV-2 Infection Among Children in the US National COVID Cohort Collaborative

Author

Blake Martin, Peter E. DeWitt, Seth Russell, Adit Anand, Katie R. Bradwell, Carolyn Bremer, Davera Gabriel, Andrew T. Girvin, Janos G. Hajagos, Julie A. McMurry, Andrew J. Neumann, Emily R. Pfaff, Anita Walden, Jacob T. Wooldridge, Yun Jae Yoo, Joel Saltz, Ken R. Gersing, Christopher G. Chute, Melissa A. Haendel, Richard Moffitt, and Tellen D. Bennett

Subjects
Male, Sociodemographic Factors, Adolescent, SARS-CoV-2, Vital Signs, COVID-19, Infant, General Medicine, Comorbidity, Severity of Illness Index, Systemic Inflammatory Response Syndrome, United States, Age Distribution, Early Diagnosis, Risk Factors, Child, Preschool, Disease Progression, Humans, Female, Child
Abstract

Importance: Understanding of SARS-CoV-2 infection in US children has been limited by the lack of large, multicenter studies with granular data. Objective: To examine the characteristics, changes over time, outcomes, and severity risk factors of children with SARS-CoV-2 within the National COVID Cohort Collaborative (N3C). Design, Setting, and Participants: A prospective cohort study of encounters with end dates before September 24, 2021, was conducted at 56 N3C facilities throughout the US. Participants included children younger than 19 years at initial SARS-CoV-2 testing. Main Outcomes and Measures: Case incidence and severity over time, demographic and comorbidity severity risk factors, vital sign and laboratory trajectories, clinical outcomes, and acute COVID-19 vs multisystem inflammatory syndrome in children (MIS-C), and Delta vs pre-Delta variant differences for children with SARS-CoV-2. Results: A total of 1068410 children were tested for SARS-CoV-2 and 167262 test results (15.6%) were positive (82882 [49.6%] girls; median age, 11.9 [IQR, 6.0-16.1] years). Among the 10245 children (6.1%) who were hospitalized, 1423 (13.9%) met the criteria for severe disease: mechanical ventilation (796 [7.8%]), vasopressor-inotropic support (868 [8.5%]), extracorporeal membrane oxygenation (42 [0.4%]), or death (131 [1.3%]). Male sex (odds ratio [OR], 1.37; 95% CI, 1.21-1.56), Black/African American race (OR, 1.25; 95% CI, 1.06-1.47), obesity (OR, 1.19; 95% CI, 1.01-1.41), and several pediatric complex chronic condition (PCCC) subcategories were associated with higher severity disease. Vital signs and many laboratory test values from the day of admission were predictive of peak disease severity. Variables associated with increased odds for MIS-C vs acute COVID-19 included male sex (OR, 1.59; 95% CI, 1.33-1.90), Black/African American race (OR, 1.44; 95% CI, 1.17-1.77), younger than 12 years (OR, 1.81; 95% CI, 1.51-2.18), obesity (OR, 1.76; 95% CI, 1.40-2.22), and not having a pediatric complex chronic condition (OR, 0.72; 95% CI, 0.65-0.80). The children with MIS-C had a more inflammatory laboratory profile and severe clinical phenotype, with higher rates of invasive ventilation (117 of 707 [16.5%] vs 514 of 8241 [6.2%]; P

Published
2022

6. Children with SARS-CoV-2 in the National COVID Cohort Collaborative (N3C)

Author

Carolyn Bremer, Andrew J. Neumann, Peter E. DeWitt, Andrew T Girvin, Katie Rebecca Bradwell, Joel H. Saltz, Yun Jae Yoo, Julie A McMurry, Blake Martin, Christopher G. Chute, Richard A. Moffitt, Jacob T. Wooldridge, Melissa Haendel, Anita Walden, Seth Russell, Tellen D. Bennett, Janos Hajagos, Emily R. Pfaff, Adit Anand, Ken R Gersing, and Davera Gabriel

Subjects
Chronic condition, Pediatrics, medicine.medical_specialty, business.industry, Incidence (epidemiology), Vital signs, Disease, medicine.disease, Comorbidity, Article, Cohort, Medicine, business, Prospective cohort study, Asthma
Abstract

ImportanceSARS-CoV-2ObjectiveTo determine the characteristics, changes over time, outcomes, and severity risk factors of SARS-CoV-2 affected children within the National COVID Cohort Collaborative (N3C)DesignProspective cohort study of patient encounters with end dates before May 27th, 2021.Setting45 N3C institutionsParticipantsChildren Main Outcomes and MeasuresCase incidence and severity over time, demographic and comorbidity severity risk factors, vital sign and laboratory trajectories, clinical outcomes, and acute COVID-19 vs MIS-C contrasts for children infected with SARS-CoV-2.Results728,047 children in the N3C were tested for SARS-CoV-2; of these, 91,865 (12.6%) were positive. Among the 5,213 (6%) hospitalized children, 685 (13%) met criteria for severe disease: mechanical ventilation (7%), vasopressor/inotropic support (7%), ECMO (0.6%), or death/discharge to hospice (1.1%). Male gender, African American race, older age, and several pediatric complex chronic condition (PCCC) subcategories were associated with higher clinical severity (p≤0.05). Vital signs (all p≤0.002) and many laboratory tests from the first day of hospitalization were predictive of peak disease severity. Children with severe (vs moderate) disease were more likely to receive antimicrobials (71% vs 32%, pCompared to those with acute COVID-19, children with MIS-C were more likely to be male, Black/African American, 1-to-12-years-old, and less likely to have asthma, diabetes, or a PCCC (p<0.04). MIS-C cases demonstrated a more inflammatory laboratory profile and more severe clinical phenotype with higher rates of invasive ventilation (12% vs 6%) and need for vasoactive-inotropic support (31% vs 6%) compared to acute COVID-19 cases, respectively (pConclusionsIn the largest U.S. SARS-CoV-2-positive pediatric cohort to date, we observed differences in demographics, pre-existing comorbidities, and initial vital sign and laboratory test values between severity subgroups. Taken together, these results suggest that early identification of children likely to progress to severe disease could be achieved using readily available data elements from the day of admission. Further work is needed to translate this knowledge into improved outcomes.

Published
2021

7. The National COVID Cohort Collaborative: Clinical Characterization and Early Severity Prediction

Author

John Muschelli, Mark M. Bissell, Melissa A. Haendel, Seth Russell, Adit Anand, Anita Walden, Richard A. Moffitt, Michele I. Morris, Eli Levitt, Davera Gabriel, Brian T. Garibaldi, Tellen D. Bennett, Benjamin Amor, Heidi Spratt, Kenneth R. Gersing, Amin Manna, Janos Hajagos, Matvey B. Palchuk, Richard L Zhu, Nabeel Qureshi, Julie A. McMurry, Carolyn Bremer, Alina Denham, Elaine L. Hill, Kristin Kostka, Andrew T Girvin, Katie Rebecca Bradwell, Justin Guinney, Jacob T. Wooldridge, Andrew E. Williams, Emily R. Pfaff, Yun Jae Yoo, Stephanie S Hong, James Brian Byrd, Xiaohan Tanner Zhang, Joel H. Saltz, Peter E. DeWitt, Zhenglong Qian, Christopher P. Austin, Andrew J. Neumann, Christopher G. Chute, Hunter Jimenez, Ramakanth Kavuluru, Harold P Lehmann, and Sandeep K. Mallipattu

Subjects
medicine.medical_specialty, business.industry, MEDLINE, Vital signs, Retrospective cohort study, Predictive analytics, Health informatics, Clinical decision support system, Article, Family medicine, Cohort, medicine, Observational study, business
Abstract

BackgroundThe majority of U.S. reports of COVID-19 clinical characteristics, disease course, and treatments are from single health systems or focused on one domain. Here we report the creation of the National COVID Cohort Collaborative (N3C), a centralized, harmonized, high-granularity electronic health record repository that is the largest, most representative U.S. cohort of COVID-19 cases and controls to date. This multi-center dataset supports robust evidence-based development of predictive and diagnostic tools and informs critical care and policy.Methods and FindingsIn a retrospective cohort study of 1,926,526 patients from 34 medical centers nationwide, we stratified patients using a World Health Organization COVID-19 severity scale and demographics; we then evaluated differences between groups over time using multivariable logistic regression. We established vital signs and laboratory values among COVID-19 patients with different severities, providing the foundation for predictive analytics. The cohort included 174,568 adults with severe acute respiratory syndrome associated with SARS-CoV-2 (PCR >99% or antigen ConclusionsThis is the first description of an ongoing longitudinal observational study of patients seen in diverse clinical settings and geographical regions and is the largest COVID-19 cohort in the United States. Such data are the foundation for ML models that can be the basis for generalizable clinical decision support tools. The N3C Data Enclave is unique in providing transparent, reproducible, easily shared, versioned, and fully auditable data and analytic provenance for national-scale patient-level EHR data. The N3C is built for intensive ML analyses by academic, industry, and citizen scientists internationally. Many observational correlations can inform trial designs and care guidelines for this new disease.

Published
2021

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