Biology subjects

McDonald, T.

Publications and source records attributed to McDonald, T..

6 recordsLinked to original sources

bioRxiv2022

SARS-CoV-2 Vaccine Booster Elicits Robust Prolonged Maternal Antibody Responses and Passive Transfer Via The Placenta And Breastmilk

BackgroundInfection during pregnancy can result in adverse outcomes for both pregnant persons and offspring. Maternal vaccination is an effective mechanism to protect both mother and neonate into post-partum. However, our understanding of passive transfer of antibodies elicited by maternal SARS-CoV-2 mRNA vaccination during pregnancy remains incomplete. ObjectiveWe aimed to evaluate the antibody responses engendered by maternal SARS-CoV-2 vaccination following initial and booster doses in maternal circulation and breastmilk to better understand passive immunization of the newborn. Study DesignWe collected longitudinal blood samples from 121 pregnant women who received SARS-CoV-2 mRNA vaccines spanning from early gestation to delivery followed by collection of blood samples and breastmilk between delivery and 12 months post-partum. During the study, 70% of the participants also received a booster post-partum. Paired maternal plasma, breastmilk, umbilical cord plasma, and newborn plasma samples were tested via enzyme-linked immunosorbent assays (ELISA) to evaluate SARS-CoV-2 specific IgG antibody levels. ResultsVaccine-elicited maternal antibodies were detected in both cord blood and newborn blood, albeit at lower levels than maternal circulation, demonstrating transplacental passive immunization. Booster vaccination significantly increased spike specific IgG antibody titers in maternal plasma and breastmilk. Finally, SARS-CoV-2 specific IgG antibodies in newborn blood correlated negatively with days post initial maternal vaccine dose. ConclusionVaccine-induced maternal SARS-CoV-2 antibodies were passively transferred to the offspring in utero via the placenta and after birth via breastfeeding. Maternal booster vaccination, regardless of gestational age at maternal vaccination, significantly increased antibody levels in breastmilk and maternal plasma, indicating the importance of this additional dose to maximize passive protection against SARS-CoV-2 infection for neonates and infants until vaccination eligibility.

immunology↗

bioRxiv2022

Single Particle Tracking With Compressive Sensing Using Progressive Refinement Method On Sparse Recovery (spt-PRIS)

Single particle tracking (SPT) is an indispensable tool for scientific studies. However, SPT for datasets with a high density of particles is still challenging, especially for the study of particle interactions where the point spread functions (PSFs) are overlapping. In this study, we present spt-PRIS, a new SPT solution where we apply compressive sensing to SPT by integrating the progressive refinement method on sparse recovery (PRIS) into the framework of the state-of-the-art SPT algorithm (uTrack). We systematically characterized and validated spt-PRIS performance using simulations, applied it to the experimental data of membrane-bound KRAS4b proteins in either 2-lipid or 8-lipid membrane supported lipid bilayers (SLB), and compared the results to the conventional method (uTrack). Our results show that spt-PRIS is effective for SPT when the data contains overlapping PSFs and provides unprecedented information about KRAS4b subpopulations. spt-PRIS is helpful for a broad range of scientific studies where precise and fast high-density localization is beneficial. spt-PRIS is also flexible for extensions for multi-species, multi-multi-channel, and multi-dimensional SPT methods with the generalization of PRIS reconstruction schemes.

biophysics↗

bioRxiv2021

Laminin switches terminal differentiation fate of human trophoblast stem cells under chemically defined culture conditions.

Human trophoblast stem cells (hTSCs) have emerged as a powerful tool to model early placental development in vitro. Analogous to the epithelial cytotrophoblast in the placenta, hTSCs can differentiate into cells of the extravillous trophoblast (EVT) lineage or the multinucleate syncytiotrophoblast (STB). Here we present a chemically defined culture system for STB and EVT differentiation of hTSCs. Notably, in contrast to current approaches, we do not utilize transforming growth factor-beta inhibitors or a passage step for EVT differentiation, or forskolin for STB formation. Strikingly, under these conditions, presence of a single additional extracellular cue - lam-inin-1 - switched the terminal differentiation of hTSCs from STB to the EVT lineage. Activation of the sphingosine-1 receptor 3 receptor (S1PR3) using a chemical agonist could drive EVT differentiation of hTSCs in the absence of exogenous laminin, albeit less efficiently. To illustrate the utility of a chemically defined culture system for mechanistic studies, we examined the role of protein kinase C (PKC) signaling during hTSC differentiation to the EVT lineage. Inhibition of PKC/{beta} signaling significantly reduced HLA-G expression and the formation of HLA-G+ mesen-chymal EVTs during hTSC differentiation mediated by laminin exposure; however, it did not prevent commitment to the EVT lineage or STB differentiation. The chemically defined culture system for hTSC differentiation established herein facilitates quantitative analysis of heterogeneity that arises during hTSC differentiation, and will enable mechanistic studies in vitro. SignificanceDespite its importance to a healthy pregnancy, early human placental development remains poorly understood. Mechanistic studies are impeded by restrictions on research with human embryos and fetal tissues, and significant differences in placentation between humans and commonly used animal models. In this context, human trophoblast stem cells (hTSCs) have emerged as attractive in vitro models for the epithelial cytotrophoblast of the early gestation human placenta. Here we describe chemically defined culture conditions for differentiation of hTSCs to the two major differentiated cell types - extravillous trophoblast and syncytiotrophoblast. These culture conditions enable in vitro studies to reveal molecular mechanisms regulating hTSC differentiation.

developmental biology↗

bioRxiv2021

Optimisation and validation of a sensitive bioanalytical method for niclosamide.

The SARS-CoV-2 pandemic has spread at an unprecedented rate, and repurposing opportunities have been intensively studied with only limited success to date. If successful, repurposing will allow interventions to become more rapidly available than development of new chemical entities. Niclosamide has been proposed as a candidate for repurposing for SARS-CoV-2 based upon the observation that it is amongst the most potent antiviral molecules evaluated in vitro. To investigate the pharmacokinetics of niclosamide, reliable, reproducible and sensitive bioanalytical assays are required. Here, a liquid chromatography tandem mass spectrometry assay is presented which was linear from 31.25-2000 ng/mL (high dynamic range) and 0.78-100 ng/mL (low dynamic range). Accuracy and precision ranged between 97.2% and 112.5%, 100.4% and 110.0%, respectively. The presented assay should have utility in preclinical evaluation of the exposure-response relationship and may be adapted for later evaluation of niclosamide in clinical trials.

pharmacology and toxicology↗

bioRxiv2020

Evidence of Absence Regression: A Binomial N-Mixture Model for Estimating Bird and Bat Fatalities at Wind Power Facilities

Estimating bird and bat fatalities caused by wind-turbine facilities is challenging when carcass counts are rare and produce counts that are either exactly zero or very near zero. The rarity of found carcasses is exacerbated when live members of a particular species are rare and when carcasses degrade quickly, are removed by scavengers, or are not detected by observers. With few observed carcass counts, common statistical methods like logistic, Poisson, or negative binomial regression are unreliable (statistically biased) and often fail to provide answers (i.e., fail to converge). Here, we propose a binomial N-mixture model that estimates fatality rates as well as the total number of carcass counts when these rates are expanded. Our model extends the evidence of absence model (Huso et al., 2015; Dalthorp, Huso, and Dail, 2017) by relating carcass deposition rates to study covariates and by incorporating terms that naturally scale counts from facilities of different sizes. Our model, which we call Evidence of Absence Regression (EoAR), can estimate the total number of birds or bats killed at a single wind energy facility or a fleet of wind energy facilities based on covariate values. Furthermore, with accurate prior distributions the models results are extremely robust to sparse data and unobserved combinations of covariate values. In this paper, we describe the model, show its low bias and high precision via computer simulation, and apply it to bat carcass counts observed at 21 wind energy facilities in Iowa.

ecology↗

bioRxiv2019

Daratumumab induces mechanisms of immune activation through CD38+ NK cell targeting

Daratumumab (Dara), a multiple myeloma (MM) therapy, is an antibody against the surface receptor CD38, which is expressed not only on plasma cells but also on NK cells and monocytes. Correlative data have highlighted the immune-modulatory role of Dara, despite the paradoxical observation that Dara regimens decrease the frequency of total NK cells. Here we show that, despite this reduction, NK cells play a pivotal role in Dara anti-MM activity. CD38 on NK cells is essential for Dara-induced immune modulation, and its expression is restricted to NK cells with effector function. We also show that Dara induces rapid CD38 protein degradation associated with NK cell activation, leaving an activated CD38-negative NK cell population. CD38+ NK cell targeting by Dara also promotes monocyte activation, inducing an increase in T cell costimulatory molecules (CD86/80) and enhancing anti-MM phagocytosis activity ex-vivo and in vivo. In support of Daras immunomodulating role, we show that MM patients that discontinued Dara therapy because of progression maintain targetable unmutated surface CD38 expression on their MM cells, but retain effector cells with impaired cellular immune function. In summary, we report that CD38+ NK cells may be an unexplored therapeutic target for priming the immune system of MM patients.

cancer biology↗