Transcriptional Control and Population Dynamics of Antiviral CD8+ T Cell Responses

Cytotoxic lymphocytes are central components of cellular immune responses to intracellular pathogens and malignancy. The transcriptional programs that support proper population dynamics for lifelong immunity are incompletely understood. Two T-box transcription factors, T-bet and Eomesodermin (Eomes), have critical roles in the development of natural killer cells and the differentiation of CD8+ T cells in response to acutely resolved infections. In both cases, these two factors support distinct but complementary cellular populations. In this thesis, we first used a recently generated reagent to examine and separate cellular populations with differential Eomes expression. We found that, while Eomes expression does not identify effector CD8+ T cells with enhanced cytotoxic potential, early Eomes expression does correlate with more efficient formation of long-lived, self-renewing central memory CD8+ T cells. This validated tool was then employed in our investigation into the population dynamics of CD8+ T cell responses during a chronic viral infection. While memory lymphocytes maintain lifelong immunity by slow self-renewal, chronic infections strain the regenerative capacity of antiviral T lymphocyte populations, leading to failure in long-term immunity. The cellular and molecular events controlling the regenerative capacity during chronic infection, however, are unknown. We demonstrate that two distinct states of virus-specific CD8+ T cells exist in chronically infected mice and humans. The opposing properties of renewal and differentiation of these CD8+ T cell populations are supported by the differential expression of T-box transcription factors, which cooperatively maintain the pool of antiviral CD8+ T cells during chronic viral infection. T-bethi cells have low intrinsic turnover but proliferate in response to persisting antigen, giving rise to Eomeshi terminal progeny. Genetic elimination of either subset results in failure to control chronic infection, suggesting that imbalance in differentiation and renewal could underlie the collapse of immunity in humans with chronic infections. Furthermore, this work demonstrates new roles for T-bet and Eomes in CD8+ T cells regarding self-renewal and terminal differentiation, highlighting how T-box transcription factors can operate in exquisitely context-dependent manners

Values and Identity in Jewish Education

This article identifies a set of values to guide the development of an ideal Jewish school; it then specifies a series of recommended organizational, curricular and instructional practices to address these values. The preface establishes the rationale for rethinking the substance and form of Jewish education in the United States

Intraocular human cytomegaloviruses of ocular diseases are distinct from those of viremia and are capable of escaping from innate and adaptive immunity by exploiting HLA-E-mediated peripheral and central tolerance

Human cytomegalovirus (HCMV) infections develop into CMV diseases that result in various forms of manifestations in local organs. CMV-retinitis is a form of CMV disease that develops in immunocompromised hosts with CMV-viremia after viruses in the peripheral circulation have entered the eye. In the HCMV genome, extensive diversification of the UL40 gene has produced peptide sequences that modulate NK cell effector functions when loaded onto HLA-E and are subsequently recognized by the NKG2A and NKG2C receptors. Notably, some HCMV strains carry UL40 genes that encode peptide sequences identical to the signal peptide sequences of specific HLA-A and HLA-C allotypes, which enables these CMV strains to escape HLA-E-restricted CD

Viral MHCI inhibition evades tissue-resident memory T cell formation and responses

Tissue-resident memory CD

The CSF in neurosarcoidosis contains consistent clonal expansion of CD8 T cells, but not CD4 T cells

The tissue-specific drivers of neurosarcoidosis remain poorly defined. To identify cerebrospinal fluid (CSF) specific, antigen-driven T and B cell responses, we performed single-cell RNA sequencing of CSF and blood cells from neurosarcoid participants coupled to T and B cell receptor sequencing. In contrast to pulmonary sarcoidosis, which is driven by CD4 T cells, we found CD8 T cell clonal expansion enriched in the neurosarcoid CSF. These CSF-enriched CD8 T cells were composed of two subsets with differential expression of EBI2, CXCR3, and CXCR4. Lastly, our data suggest that IFNγ signaling may distinguish neurosarcoidosis from other neurological disorders

Crowdsourced assessment of surgical skill proficiency in cataract surgery

OBJECTIVE: To test whether crowdsourced lay raters can accurately assess cataract surgical skills. DESIGN: Two-armed study: independent cross-sectional and longitudinal cohorts. SETTING: Washington University Department of Ophthalmology. PARTICIPANTS AND METHODS: Sixteen cataract surgeons with varying experience levels submitted cataract surgery videos to be graded by 5 experts and 300+ crowdworkers masked to surgeon experience. Cross-sectional study: 50 videos from surgeons ranging from first-year resident to attending physician, pooled by years of training. Longitudinal study: 28 videos obtained at regular intervals as residents progressed through 180 cases. Surgical skill was graded using the modified Objective Structured Assessment of Technical Skill (mOSATS). Main outcome measures were overall technical performance, reliability indices, and correlation between expert and crowd mean scores. RESULTS: Experts demonstrated high interrater reliability and accurately predicted training level, establishing construct validity for the modified OSATS. Crowd scores were correlated with (r = 0.865, p \u3c 0.0001) but consistently higher than expert scores for first, second, and third-year residents (p \u3c 0.0001, paired t-test). Longer surgery duration negatively correlated with training level (r = -0.855, p \u3c 0.0001) and expert score (r = -0.927, p \u3c 0.0001). The longitudinal dataset reproduced cross-sectional study findings for crowd and expert comparisons. A regression equation transforming crowd score plus video length into expert score was derived from the cross-sectional dataset (r CONCLUSIONS: Crowdsourced rankings correlated with expert scores, but were not equivalent; crowd scores overestimated technical competency, especially for novice surgeons. A novel approach of adjusting crowd scores with surgery duration generated a more accurate predictive model for surgical skill. More studies are needed before crowdsourcing can be reliably used for assessing surgical proficiency

Professional identity in nursing: UK students' explanations for poor standards of care

Research concludes that professional socialisation in nursing is deeply problematic because new recruits start out identifying with the profession’s ideals but lose this idealism as they enter and continue to work in the profession. This study set out to examine the topic focussing on the development of professional identity. Six focus groups were held with a total of 49 2nd and 3rd year BSc nursing students studying at a university in London, UK and their transcripts were subject to discourse analysis. Participants’ talk was strongly dualistic and inflected with anxiety. Participants identified with caring as an innate characteristic. They described some qualified nurses as either not possessing this characteristic or as having lost it. They explained strategies for not becoming corrupted in professional practice. Their talk enacted distancing from ‘bad’ qualified nurses and solidarity with other students. Their talk also featured cynicism. Neophyte nurses’ talk of idealism and cynicism can be understood as identity work in the context of anxiety inherent in the work of nurses and in a relatively powerless position in the professional healthcare hierarchy

An improved measurement of muon antineutrino disappearance in MINOS

We report an improved measurement of muon anti-neutrino disappearance over a distance of 735km using the MINOS detectors and the Fermilab Main Injector neutrino beam in a muon anti-neutrino enhanced configuration. From a total exposure of 2.95e20 protons on target, of which 42% have not been previously analyzed, we make the most precise measurement of the anti-neutrino "atmospheric" delta-m squared = 2.62 +0.31/-0.28 (stat.) +/- 0.09 (syst.) and constrain the anti-neutrino atmospheric mixing angle >0.75 (90%CL). These values are in agreement with those measured for muon neutrinos, removing the tension reported previously.Comment: 5 pages, 4 figures. In submission to Phys.Rev.Let

Improved Search for Muon-Neutrino to Electron-Neutrino Oscillations in MINOS

We report the results of a search for ν_e appearance in a ν_μ beam in the MINOS long-baseline neutrino experiment. With an improved analysis and an increased exposure of 8.2×10^(20) protons on the NuMI target at Fermilab, we find 2sin^2(θ_(23))sin^2(2θ_(13))<0.12(0.20) at 90% confidence level for δ=0 and the normal (inverted) neutrino mass hierarchy, with a best-fit of 2sin^2(θ_(23))sin^2(2θ_(13))=0.041^(+0.047)_(-0.031)(0.079^(+0.071)_(-0.053). The θ_(13)= 0 hypothesis is disfavored by the MINOS data at the 89% confidence level