Insights into T Cell Recognition of Antigen: Significance of Two-Dimensional Kinetic Parameters

The T cell receptor (TCR) interacts with peptide-major histocompatibility complex (pMHC) to enable T cell development and trigger adaptive immune responses. For this reason, TCR:pMHC interactions have been intensely studied for over two decades. However, the details of how various binding parameters impact T cell activation remain elusive. Most measurements were made using recombinant proteins by surface plasmon resonance, a three-dimensional (3D) technique in which fluid-phase receptors and ligands are removed from their cellular environment. This approach found TCR:pMHC interactions with relatively low affinities and slow off-rates for agonist peptides. Newer generation techniques have analyzed TCR:pMHC interactions in two dimensions (2D), with both proteins anchored in apposing plasma membranes. These approaches reveal in situ TCR:pMHC interaction kinetics that are of high affinity and exhibit rapid on- and off-rates upon interaction with agonist ligands. Importantly, 2D binding parameters correlate better with T cell functional responses to a spectrum of ligands than 3D measures

Low 2-Dimensional CD4 T Cell Receptor Affinity for Myelin Sets in Motion Delayed Response Kinetics

T cells recognizing self-peptides that mediate autoimmune disease and those that are responsible for efficacious immunity against pathogens may differ in affinity for antigen due to central and peripheral tolerance mechanisms. Here we utilize prototypical self-reactive (myelin) and viral-specific (LCMV) T cells from T cell receptor (TCR) transgenic mice (2D2 and SMARTA, respectively) to explore affinity differences. The T cells responsive to virus possessed >10,000 fold higher 2D affinity as compared to the self-reactive T cells. Despite their dramatically lower affinity for their cognate ligand, 2D2 T cells respond with complete, albeit delayed, activation (proliferation and cytokine production). SMARTA activation occurs rapidly, achieving peak phosphorylation of p38 (1 minute), Erk (30 minutes), and Jun (3 hours) as well as CD69 and CD25 upregulation (3 and 6 hours, respectively), with a corresponding early initiation of proliferation. 2D2 stimulation with MOG results in altered signaling – no phospho-Erk or phospho-p38 accumulation, significantly delayed activation kinetics of Jun (12 hours), and delayed but sustained SHP-1 activity – as well as delayed CD69 and CD25 expression (12–24 hours), and slow initiation of proliferation. This delay was not intrinsic to the 2D2 T cells, as a more potent antigen with >100-fold increased 2D affinity restored rapid response kinetics in line with those identified for the viral antigen. Taken together, these data demonstrate that time can offset low TCR affinity to attain full activation and suggest a mechanism by which low affinity T cells participate in autoimmune disease

Contraceptive preferences and unmet need for contraception in midlife women: where are the data?

Abstract This commentary discusses the limited availability of information on contraceptive preferences and unmet need for contraception among midlife women in both high and low income countries. Given that risk of pregnancy continues until women reach menopause and given the increased risk of pregnancy complications, elective abortion, and maternal mortality in women aged 45 to 54 years old, increased focus on gathering basic data on midlife women’s preferences and unmet need is warranted.https://deepblue.lib.umich.edu/bitstream/2027.42/138119/1/40695_2017_Article_26.pd

Contraceptive preferences and unmet need for contraception in midlife women: where are the data?

Abstract This commentary discusses the limited availability of information on contraceptive preferences and unmet need for contraception among midlife women in both high and low income countries. Given that risk of pregnancy continues until women reach menopause and given the increased risk of pregnancy complications, elective abortion, and maternal mortality in women aged 45 to 54 years old, increased focus on gathering basic data on midlife women’s preferences and unmet need is warranted.https://deepblue.lib.umich.edu/bitstream/2027.42/138119/1/40695_2017_Article_26.pd

Genetic Predisposition Impacts Clinical Changes in a Lifestyle Coaching Program.

Both genetic and lifestyle factors contribute to an individual\u27s disease risk, suggesting a multi-omic approach is essential for personalized prevention. Studies have examined the effectiveness of lifestyle coaching on clinical outcomes, however, little is known about the impact of genetic predisposition on the response to lifestyle coaching. Here we report on the results of a real-world observational study in 2531 participants enrolled in a commercial Scientific Wellness program, which combines multi-omic data with personalized, telephonic lifestyle coaching. Specifically, we examined: 1) the impact of this program on 55 clinical markers and 2) the effect of genetic predisposition on these clinical changes. We identified sustained improvements in clinical markers related to cardiometabolic risk, inflammation, nutrition, and anthropometrics. Notably, improvements in HbA1c were akin to those observed in landmark trials. Furthermore, genetic markers were associated with longitudinal changes in clinical markers. For example, individuals with genetic predisposition for higher LDL-C had a lesser decrease in LDL-C on average than those with genetic predisposition for average LDL-C. Overall, these results suggest that a program combining multi-omic data with lifestyle coaching produces clinically meaningful improvements, and that genetic predisposition impacts clinical responses to lifestyle change

Longitudinal analysis reveals transition barriers between dominant ecological states in the gut microbiome.

The Pioneer 100 Wellness Project involved quantitatively profiling 108 participants\u27 molecular physiology over time, including genomes, gut microbiomes, blood metabolomes, blood proteomes, clinical chemistries, and data from wearable devices. Here, we present a longitudinal analysis focused specifically around the Pioneer 100 gut microbiomes. We distinguished a subpopulation of individuals with reduced gut diversity, elevated relative abundance of the genus Prevotella, and reduced levels of the genus Bacteroides We found that the relative abundances of Bacteroides and Prevotella were significantly correlated with certain serum metabolites, including omega-6 fatty acids. Primary dimensions in distance-based redundancy analysis of clinical chemistries explained 18.5% of the variance in bacterial community composition, and revealed a Bacteroides/Prevotella dichotomy aligned with inflammation and dietary markers. Finally, longitudinal analysis of gut microbiome dynamics within individuals showed that direct transitions between Bacteroides-dominated and Prevotella-dominated communities were rare, suggesting the presence of a barrier between these states. One implication is that interventions seeking to transition between Bacteroides- and Prevotella-dominated communities will need to identify permissible paths through ecological state-space that circumvent this apparent barrier

The Vehicle, Fall 2007

Table of Contents Is This Thing On?Nichole D\u27Antoniopage 1 Death Came KnockingJacob Dawsonpage 5 Awaiting DecemberRebecca Griffithpage 9 ginamarieElizabeth Hoodpage 11 She LongsJennifer O\u27Neilpage 12 ForgottenStephanie Drozdpage 13 Art House WomanGreg Harrellpage 14 Young Woman OlderAmanda Vealepage 15 FirstRebecca Griffithpage 17 FlowJacob Dawsonpage 19 Am Animal AwareDanielle Meyerpage 20 Geneva 04\u27Stephanie Guyerpage 21 Poland, 1942.Jennifer O\u27Neilpage 22 Witness to the Atrophy of ForestsDanielle Meyerpage 23 Helvellyn IJacob Fosterpage 24 Three Out of Five Ain\u27t BadThomas McElweepage 25 FarceAmanda Vealepage 31 Strength of EmotionJennifer O\u27Neilpage 32 About the Authors Art Submissions Prerequisite for a RequiemJenna Smithcover Girl 3Jenna Smithpage 14 ManJenna Smithpage 16 Give Peace a ChanceMegan Mathypage 16 GraceJennifer O\u27Neilpage 20 Oh, the Places You\u27ll Go!Megan Mathypage 23https://thekeep.eiu.edu/vehicle/1086/thumbnail.jp

The Vehicle, Fall 2007

Table of Contents Is This Thing On?Nichole D\u27Antoniopage 1 Death Came KnockingJacob Dawsonpage 5 Awaiting DecemberRebecca Griffithpage 9 ginamarieElizabeth Hoodpage 11 She LongsJennifer O\u27Neilpage 12 ForgottenStephanie Drozdpage 13 Art House WomanGreg Harrellpage 14 Young Woman OlderAmanda Vealepage 15 FirstRebecca Griffithpage 17 FlowJacob Dawsonpage 19 Am Animal AwareDanielle Meyerpage 20 Geneva 04\u27Stephanie Guyerpage 21 Poland, 1942.Jennifer O\u27Neilpage 22 Witness to the Atrophy of ForestsDanielle Meyerpage 23 Helvellyn IJacob Fosterpage 24 Three Out of Five Ain\u27t BadThomas McElweepage 25 FarceAmanda Vealepage 31 Strength of EmotionJennifer O\u27Neilpage 32 About the Authors Art Submissions Prerequisite for a RequiemJenna Smithcover Girl 3Jenna Smithpage 14 ManJenna Smithpage 16 Give Peace a ChanceMegan Mathypage 16 GraceJennifer O\u27Neilpage 20 Oh, the Places You\u27ll Go!Megan Mathypage 23https://thekeep.eiu.edu/vehicle/1086/thumbnail.jp

Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection (BATCH): Protocol for a randomised controlled trial

Introduction Procalcitonin (PCT) is a biomarker more specific for bacterial infection and responds quicker than other commonly used biomarkers such as C reactive protein, but is not routinely used in the National Health Service (NHS). Studies mainly in adults show that using PCT to guide clinicians may reduce antibiotic use, reduce hospital stay, with no associated adverse effects such as increased rates of hospital re-admission, incomplete treatment of infections, relapse or death. A review conducted for National Institute for Health and Care Excellence recommends further research on PCT testing to guide antibiotic use in children.Methods and analysis Biomarker-guided duration of Antibiotic Treatment in Children Hospitalised with confirmed or suspected bacterial infection is a multi-centre, prospective, two-arm, individually Randomised Controlled Trial (RCT) with a 28-day follow-up and internal pilot. The intervention is a PCT-guided algorithm used in conjunction with best practice. The control arm is best practice alone. We plan to recruit 1942 children, aged between 72 hours and up to 18 years old, who are admitted to the hospital and being treated with intravenous antibiotics for suspected or confirmed bacterial infection. Coprimary outcomes are duration of antibiotic use and a composite safety measure. Secondary outcomes include time to switch from broad to narrow spectrum antibiotics, time to discharge, adverse drug reactions, health utility and cost-effectiveness. We will also perform a qualitative process evaluation. Recruitment commenced in June 2018 and paused briefly between March and May 2020 due to the COVID-19 pandemic