Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation

Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios⁺ T cells and autoantibodies

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1ᴬⁿᵃᵉᶠ, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1ᴬⁿᵃᵉᶠ mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios⁺ PD-1⁺ CD4⁺ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1ᴬⁿᵃᵉᶠ is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1ᴬⁿᵃᵉᶠ naïve CD4⁺ T cells. CD44 expression, CD4⁺ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1ᴬⁿᵃᵉᶠMtorᶜʰⁱⁿᵒ double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1ᴬⁿᵃᵉᶠ T cell dysregulation

Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios+ T cells and autoantibodies

Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1(Anaef), with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1(Anaef) mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44(hi) Helios(+) PD-1(+) CD4(+) T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1(Anaef) is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1(Anaef) naïve CD4(+) T cells. CD44 expression, CD4(+) T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1(Anaef)Mtor(chino) double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1(Anaef) T cell dysregulation. DOI: http://dx.doi.org/10.7554/eLife.01020.00

An SAS Macro for Implementing the Modified Bollen–Stine Bootstrap for Missing Data: Implementing the Bootstrap Using Existing Structural Equation Modeling Software

The Bollen–Stine bootstrap can be used to correct for standard error and fit statistic bias that occurs in structural equation modeling (SEM) applications due to nonnormal data. The purpose of this article is to demonstrate the use of a custom SAS macro program that can be used to implement the Bollen–Stine bootstrap with existing SEM software. Although this article focuses on missing data, the macro can be used with complete data sets as well. A series of heuristic analyses are presented, along with detailed programming instructions for each of the commercial SEM software packages

The Relative Performance of Full Information Maximum Likelihood Estimation for Missing Data in Structural Equation Models

A Monte Carlo simulation examined the performance of 4 missing data methods in structural equation models: full information maximum likelihood (FIML), listwise deletion, pairwise deletion, and similar response pattern imputation. The effects of 3 independent variables were examined (factor loading magnitude, sample size, and missing data rate) on 4 outcome measures: convergence failures, parameter estimate bias, parameter estimate efficiency, and model goodness of fit. Results indicated that FIML estimation was superior across all conditions of the design. Under ignorable missing data conditions (missing completely at random and missing at random), FIML estimates were unbiased and more efficient than the other methods. In addition, FIML yielded the lowest proportion of convergence failures and provided near-optimal Type 1 error rates across both simulations

The Henry-Heilbronner Index: a 15-item empirically derived MMPI-2 subscale for identifying probable malingering in personal injury litigants and disability claimants.

A new 15-item MMPI-2 subscale, the Henry-Heilbronner Index (HHI), representing a pseudosomatic factor, was empirically derived from both the 43-item Lees-Haley Fake Bad Scale (FBS) and the 17-item Shaw and Matthews\u27 Pseudoneurologic Scale (PNS). The HHI was superior to both the FBS and PNS in identification of symptom exaggeration in personal injury litigants and disability claimants compared to non-litigating head-injured controls. Logistic regression analyses revealed that a cutscore of \u3e or = 8 on the HHI was associated with good specificity (89%) and sensitivity (80%). These results suggest that the HHI may be useful in identifying personal injury litigants and disability claimants who exaggerate, overreport, or malinger physical symptoms on the MMPI-2 related to their current health and/or litigation status

Comparison of the MMPI-2 Restructured Demoralization Scale, Depression Scale, and Malingered Mood Disorder Scale in Identifying Non-Credible Symptom Reporting in Personal Injury Litigants and Disability Claimants.

A known groups design compared the ability of the 24-item MMPI-2 Restructured Clinical Demoralization Scale (RCd), the 57-item Depression Scale (Scale 2), and the 15-item Malingered Mood Disorder Scale (MMDS) to identify non-credible symptom response sets in 84 personal injury litigants and disability claimants compared to 77 non-litigating head-injured controls. All three scales showed large effect sizes (\u3e0.80). Scale 2 was associated with the largest effect size (2.19), followed by the MMDS (1.65), and the RCd (0.85). Logistic regression analyses revealed that a cutscore of \u3e or =28 on the 57-item Scale 2 was associated with high specificity (96.1%) and sensitivity (76.2%), while a cutscore of \u3e or =16 on the 24-item RCd was less accurate (87% specificity and 50% sensitivity). Cutscores for the MMDS were not calculated as they were reported in a previous study. Results indicated that like the 15-item MMDS, the 57-item MMPI-2 Scale 2 may provide another empirically derived index with known error rates upon which examiners may rely to investigate hypotheses relative to exaggeration of illness-related behavior and impression management in forensic contexts involving PI litigants and disability claimants