Post-acute sequelae of COVID-19 (PASC) represent an emerging global crisis. However, quantifiable risk factors for PASC and their biological associations are poorly resolved. We executed a deep ...multi-omic, longitudinal investigation of 309 COVID-19 patients from initial diagnosis to convalescence (2–3 months later), integrated with clinical data and patient-reported symptoms. We resolved four PASC-anticipating risk factors at the time of initial COVID-19 diagnosis: type 2 diabetes, SARS-CoV-2 RNAemia, Epstein-Barr virus viremia, and specific auto-antibodies. In patients with gastrointestinal PASC, SARS-CoV-2-specific and CMV-specific CD8+ T cells exhibited unique dynamics during recovery from COVID-19. Analysis of symptom-associated immunological signatures revealed coordinated immunity polarization into four endotypes, exhibiting divergent acute severity and PASC. We find that immunological associations between PASC factors diminish over time, leading to distinct convalescent immune states. Detectability of most PASC factors at COVID-19 diagnosis emphasizes the importance of early disease measurements for understanding emergent chronic conditions and suggests PASC treatment strategies.
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•Longitudinal multi-omics associate PASC with auto-antibodies, viremia, and comorbidities•Reactivation of latent viruses during initial infection may contribute to PASC•Subclinical auto-antibodies negatively correlate with anti-SARS-CoV-2 antibodies•Gastrointestinal PASC uniquely present with post-acute expansion of cytotoxic T cells
By correlating patient symptoms with in-depth profiling of blood cells and plasma components throughout COVID-19 infection, this study identifies factors that may predict sustained disease.
Voltage-gated K
channels function in macromolecular complexes with accessory subunits to regulate brain function. Here, we describe a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 ...(Pin1)-dependent mechanism that regulates the association of the A-type K
channel subunit Kv4.2 with its auxiliary subunit dipeptidyl peptidase 6 (DPP6), and thereby modulates neuronal excitability and cognitive flexibility. We show that activity-induced Kv4.2 phosphorylation triggers Pin1 binding to, and isomerization of, Kv4.2 at the pThr
-Pro motif, leading to the dissociation of the Kv4.2-DPP6 complex. We generated a novel mouse line harboring a knock-in Thr607 to Ala (Kv4.2TA) mutation that abolished dynamic Pin1 binding to Kv4.2. CA1 pyramidal neurons of the hippocampus from these mice exhibited altered Kv4.2-DPP6 interaction, increased A-type K
current, and reduced neuronal excitability. Behaviorally, Kv4.2TA mice displayed normal initial learning but improved reversal learning in both Morris water maze and lever press paradigms. These findings reveal a Pin1-mediated mechanism regulating reversal learning and provide potential targets for the treatment of neuropsychiatric disorders characterized by cognitive inflexibility.
This article reviews current medical literature to assess the benefits and drawbacks of virtual interviews for radiology residencies as well as the downstream effects of these changes, best ...practices, and potential future recruitment methods. Topics covered include the effects of remote recruitment in promoting accessibility and applicant diversity and equality as well as fiscal, environmental, and time savings in combination with technical challenges, the complications of over application, challenges in assessment of program culture and location, impact on morale, and hidden financial and emotional costs. Learnings from other medical specialties are highlighted in addition to the process of signaling, guidelines for conducting and participating in virtual interviews, and matters for future consideration.
•Strategies to maximize rigor and reproducibility in rodent behavioral assays.•Replicability of translational rodent models as preclinical research tools.•Key methods for one example, the novel ...object recognition cognitive test.•Extensive literature cited will refer the reader to detailed appropriate methods.
Behavioral neuroscience research incorporates the identical high level of meticulous methodologies and exacting attention to detail as all other scientific disciplines. To achieve maximal rigor and reproducibility of findings, well-trained investigators employ a variety of established best practices. Here we explicate some of the requirements for rigorous experimental design and accurate data analysis in conducting mouse and rat behavioral tests. Novel object recognition is used as an example of a cognitive assay which has been conducted successfully with a range of methods, all based on common principles of appropriate procedures, controls, and statistics. Directors of Rodent Core facilities within Intellectual and Developmental Disabilities Research Centers contribute key aspects of their own novel object recognition protocols, offering insights into essential similarities and less-critical differences. Literature cited in this review article will lead the interested reader to source papers that provide step-by-step protocols which illustrate optimized methods for many standard rodent behavioral assays. Adhering to best practices in behavioral neuroscience will enhance the value of animal models for the multiple goals of understanding biological mechanisms, evaluating consequences of genetic mutations, and discovering efficacious therapeutics.
Objective
Osteoporosis is a skeletal disorder characterized by low bone mass and increased bone fragility associated with aging, menopause, smoking, obesity, or diabetes. Persistent inflammation has ...been identified as an instigating factor in progressive bone loss. In addition to the role of fibrin in coagulation, inordinate fibrin deposition within a tissue matrix results in increased local inflammation. Given that fibrin accumulation is a hallmark of osteoporosis‐related comorbidities, we undertook this study to test the hypothesis that persistent fibrin deposition causes inflammatory osteoporosis.
Methods
Multiple imaging modalities, bone integrity metrics, and histologic analyses were employed to evaluate skeletal derangements in relation to fibrin deposition, circulating fibrinogen levels, and systemic markers of inflammation in mice that were plasminogen deficient and in plasminogen‐deficient mice that were concomitantly either fibrinogen deficient or carrying a mutant form of fibrinogen lacking the αMβ2 binding motif.
Results
Mice generated with a genetic deficit in the key fibrinolytic protease, plasmin, uniformly developed severe osteoporosis. Furthermore, the development of osteoporosis was fibrin(ogen) dependent, and the derangements in the bone remodeling unit were mechanistically tied to fibrin(ogen)‐mediated activation of osteoclasts via activation of the leukocyte integrin receptor αMβ2 on monocytes and secondary stimulation of osteoblasts by RANKL. Notably, the genetic elimination of fibrin(ogen) or the expression of a mutant form of fibrinogen retaining clotting function but lacking the αMβ2 binding motif prevented the degenerative skeletal phenotypes, resulting in normal local and systemic cytokine levels.
Conclusion
Taken together, these data reveal for the first time that fibrin promotes inflammation‐driven systemic osteoporosis, which suggests a novel association between hemostasis, inflammation, and bone biology.
Over the past two decades, colleges of education along with a number of national organizations and specialized professional associations have sought to improve educational administration programs ...through the incorporation of a broad policy framework designed to develop socially just leaders. Central to the growth of these new leaders is a commitment to acknowledge and embrace difference and to create educational spaces within which all children can learn. As the notion of social justice within education has been evolving, certain students, particularly those with disabilities, have been railing against persistent inequities within schools. Special education has emerged as one of the most litigious issues that school leaders must confront in their daily practice. Nevertheless, content related to special education and special education law has been a long neglected area within university-based administrator preparation programs and has been strangely absent in conversations relevant to the creation of administrator preparation programs that embrace a social justice model of leadership. Beginning with the current literature base of social justice and leadership preparation in special education and special education law, and using the recently revised Educational Leadership Constituents Council Advanced Programs in Educational Leadership Standards for building-level administrators for context, this article proposes an imperative to include curriculum content and leadership training that embraces and honors the inclusion of students in K-12 special education programs and enables building-level administrators to fulfill their role as socially just leaders.
Abstract Osteosarcoma is the most common primary malignant tumor of bone and accounts for half of all primary skeletal malignancies in children and teenagers. The prognosis for patients who fail or ...progress on first-line chemotherapy protocols is poor, therefore, additional adjuvant therapeutic strategies are needed. A recent feasibility study has demonstrated that the nitrogen-containing bisphosphonate zoledronic acid (ZOL) can be combined safely with conventional chemotherapy. However, the pharmacodynamics of bisphosphonate therapy is not well characterized. Osteosarcoma is a highly angiogenic tumor. Recent reports of the anti-angiogenic effects of bisphosphonates prompted us to determine whether nitrogen-containing bisphosphonate (ZOL and alendronate) treatment attenuates osteosarcoma growth by inhibition of osteoclast activity, tumor-mediated angiogenesis, or direct inhibitory effects on osteosarcoma. Here, we demonstrate that bisphosphonates directly inhibit VEGFR2 expression in endothelial cells, as well as endothelial cell proliferation and migration. Additionally, bisphosphonates also decrease VEGF-A expression in osteosarcoma (K7M3) cells, resulting in reduced stimulation of endothelial cell migration in co-culture assays. ZOL also decreases VEGFR1 expression in aggressive osteosarcoma cell lines (K7M3, 143B) and induces apoptosis of these cells, but has negligible effects on less aggressive osteosarcoma cell lines (K12 and TE85). In vivo ZOL treatment results in significant reduction in osteosarcoma-initiated angiogenesis and tumor growth in a murine model of osteosarcoma. In conclusion, bisphosphonates have diverse growth inhibitory effects on osteosarcoma through: (1) activation of apoptosis and inhibition of cell proliferation, (2) inhibition of VEGF-A and VEGFR1 expression by tumor cells, (3) inhibition of tumor-induced angiogenesis, and (4) direct inhibitory actions on endothelial cells.
This review examines ethnicity reporting in three autism-related journals (
Autism, Focus on Autism and Other Developmental Disabilities,
and
Journal of Autism and Developmental Disorders
) over a ...6-year period. A comprehensive multistep search of articles is used to identify ethnicity as a demographic variable in these three journals. Articles that identified research participants’ ethnicity were further analyzed to determine the impact of ethnicity as a demographic variable on findings of each study. The results indicate that ethnicity has not been adequately reported in these three autism related journals even though previous recommendations have been made to improve inadequacies of descriptive information of research participants in autism research (Kistner and Robbins in J Autism Dev Disord 16:77–82,
1986
). Implications for the field of autism spectrum disorders are discussed in addition to further recommendations for future research.
Students in their second year of the Vanderbilt Program of Interprofessional Learning (VPIL) complete team-based quality improvement (QI) projects in their assigned clinic as part of the core ...curriculum. This report describes the creation and implementation of the student teams' QI curriculum and investigates how clinical preceptors view the project impact. Between 2012-2019, the VPIL teams designed and implemented 69 improvement projects. Improvement projects fell primarily into three categories: improving clinic care delivery (
= 25, 36%), patient education and health coaching (
= 21, 30%), and quality measures such as screening tests/prophylaxis (
= 10, 14%). Clinic preceptors received a survey about the sustainability and effectiveness of the projects. Survey feedback was received from 44/69 (64%) preceptors. Many (70%) projects resulted in perceived improvements, and some projects (34%) had improvements that are still in use. Despite barriers and challenges, interprofessional student teams can successfully learn the basics of QI and work together to design and implement a project. These projects have the potential to make meaningful changes in clinic practices and are helpful to the clinic preceptors.
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