Biology subjects

Parikh, U. M.

Publications and source records attributed to Parikh, U. M..

4 recordsLinked to original sources

bioRxiv2023

SARS-CoV-2 monoclonal antibody treatment followed by vaccination shifts human memory B cell epitope recognition suggesting antibody feedback

Therapeutic anti-SARS-CoV-2 monoclonal antibodies (mAbs) have been extensively studied in humans, but the impact on immune memory of mAb treatment during an ongoing immune response has remained unclear. Here, we evaluated the effect of infusion of the anti-SARS-CoV-2 spike receptor binding domain (RBD) mAb bamlanivimab on memory B cells (MBCs) in SARS-CoV-2-infected individuals. Bamlanivimab treatment skewed the repertoire of memory B cells targeting Spike towards non-RBD epitopes. Furthermore, the relative affinity of RBD memory B cells was weaker in mAb-treated individuals compared to placebo-treated individuals over time. Subsequently, after mRNA COVID-19 vaccination, memory B cell differences persisted and mapped to a specific defect in recognition of the class II RBD site, the same RBD epitope recognized by bamlanivimab. These findings indicate a substantial role of antibody feedback in regulating human memory B cell responses, both to infection and vaccination. These data indicate that mAb administration can promote alterations in the epitopes recognized by the B cell repertoire, and the single administration of mAb can continue to determine the fate of B cells in response to additional antigen exposures months later. SIGNIFICANCE STATEMENTEvaluating the therapeutic use of monoclonal antibodies during SARS-CoV-2 infection requires a comprehensive understanding of their impact on B cell responses at the cellular level and how these responses are shaped after vaccination. We report for the first time the effect of bamlanivimab on SARS-CoV-2 specific human memory B cells of COVID-19 infected humans receiving, or not, mRNA immunization.

immunology↗

bioRxiv2023

Early antiviral CD4 and CD8 T cell responses are associated with upper respiratory tract clearance of SARS-CoV-2

T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, samples were assessed for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18-86 years old, approximately half of whom were considered high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4 and CD8 T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4 T cell and CD8 T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4 and CD8 T cells during acute COVID-19.

immunology↗

bioRxiv2022

Defining Predictors of Successful Early Career to Independent Funding Conversion Among Surgeon-Scientists

IntroductionThe National Institutes of Health (NIH) provides research funding to scientists at different stages of their career through a range of grant awards. Early-stage researchers are eligible for mentored Career Development (K) awards, to aid in the transition to independent NIH funding. Factors such as education, subspecialty, and time to funding have been studied as predictors of obtaining independent awards in nonsurgical specialties. However, in surgery, the importance of these factors has yet to be clearly elucidated. We aim to identify predictors of K to independent award conversion among surgeon-scientists to understand how to better support early-stage researchers transitioning to independent careers. Materials and MethodsIn July 2020, the NIH Research Portfolio Online Reporting Tools database was queried for individuals affiliated with surgery departments who received NIH Career Development Awards (between 2000 and 2020). The following factors were analyzed: publications, institution, degrees, year of completion of training, and gender. ResultsBetween 2000 and 2020, 228 surgeons received K Awards, of which 44% transitioned to independent funding. On average, surgeons received a K award 4.0 years after completing fellowship training and an independent award 5.4 years after receiving a K grant. The time to receiving a K award was predictive of successfully achieving independent funding, and those with independent funding had a significantly greater number of publications per year of their K-award. ConclusionSurgeons successful in transitioning to independent NIH awards do so approximately 9 years after finishing fellowship. Publication track record is the main factor associated with successful conversion from a K award. Surgery departments should emphasize manuscript productivity and develop strategies to minimize time to independent funding to help K-awardees begin independent research careers.

scientific communication and education↗

bioRxiv2020

Phenotypic Differences in Adult and Fetal Dermal Fibroblast Responses to Mechanical Tension

ObjectiveFetal regenerative wound healing is characterized by hyaluronan(HA)-rich microenvironment and fibroblasts that produce pericellular matrices(PCM) abundant in high molecular weight HA. Recent studies showed that while small wounds in fetal skin heal regeneratively, large wounds heal with fibrosis. We posit large wounds generate higher mechanical tension which alters HA metabolism in the fetal fibroblasts and lead to a pro-fibrotic phenotype. ApproachC57BL/6J murine fetal (FFB; E14.5) and adult (AFB; 8wk) dermal fibroblasts were subjected to +/-10% tonic strain. Changes in PCM, HA enzymes and molecular weight, and fibrotic gene expression were measured. ResultsFFB pericellular matrix reduced upon exposure to increased tension, and the HA profile shifted from high to lower molecular weight. Under static conditions, AFB had higher expression of HA synthases (HAS) 1 and 2 and degradation enzymes KIAA1199, HYAL1, and TMEM2 than FFB, suggesting more HA turnover in AFB. Tension resulted in an increase in HAS1, HAS3, KIAA1199, and HYAL2 expression and a decrease in HAS2 and TMEM2 expression in FFB. CD26, a marker associated with scar production, increased in FFB under tension, along with altered fibrotic gene expression profile and reorganized cytoskeletal f-actin and increased -SMA that resembled AFB. InnovationThis study elucidates the differences in how biomechanical tension alters HA metabolism and fibrotic phenotype of FFB vs AFB, providing further understanding of the fetal regenerative wound healing phenotype. ConclusionUnderstanding the intrinsic differences in HA metabolism and fibrotic phenotype among FFB and AFB in response to wound mechanical stimuli may yield new insights to promote regenerative wound healing.

molecular biology↗