Out-of-Sequence Signal 3 Paralyzes Primary CD4+ T-Cell-Dependent Immunity

SummaryPrimary T cell activation involves the integration of three distinct signals delivered in sequence: (1) antigen recognition, (2) costimulation, and (3) cytokine-mediated differentiation and expansion. Strong immunostimulatory events such as immunotherapy or infection induce profound cytokine release causing “bystander” T cell activation, thereby increasing the potential for autoreactivity and need for control. We show that during strong stimulation, a profound suppression of primary CD4+ T-cell-mediated immune responses ensued and was observed across preclinical models and patients undergoing high-dose interleukin-2 (IL-2) therapy. This suppression targeted naive CD4+ but not CD8+ T cells and was mediated through transient suppressor of cytokine signaling-3 (SOCS3) inhibition of the STAT5b transcription factor signaling pathway. These events resulted in complete paralysis of primary CD4+ T cell activation, affecting memory generation and induction of autoimmunity as well as impaired viral clearance. These data highlight the critical regulation of naive CD4+ T cells during inflammatory conditions

Evolution of Safeguards - An Expert-driven Approach to Acquisition Path Analysis

The IAEA’s Department of Safeguards has embarked on an evolutionary process to more fully develop and apply the State-Level Concept (SLC) for safeguards implementation. This concept makes use of all safeguards-relevant information available in order to focus and prioritize its safeguards activities for a State. A key component is the development of a State-level Approach (SLA) which consists of analyzing acquisition paths, establishing and prioritizing technical objectives, and identifying applicable safeguards measures. The Next Generation Safeguard Initiative of the National Nuclear Security Administration, Office of Nonproliferation and International Security, has supported LANL's assessment of alternatives for SLA development. Our proposed methodology is comprised of three activities: network modeling, network analysis, and strategic assessment. The network modeling step assesses and formalizes the State’s nuclear capabilities in terms of plausible proliferation paths. The network analysis step gives a ranking of paths in terms of their attractiveness under various assumptions. Finally, the strategic assessment evaluates the State’s proliferation alternatives given a set of derived technical objectives and the implementation of related safeguards measures. In this paper, we examine a hypothetical State model to test our methodology’s performance. In this context, we identified and prioritized the hypothetical State’s acquisition paths according to notional proliferation strategies. State Specific Factors were examined in terms of their impact on path priorities. We examined methods for determining technical objectives contingent upon meeting designated performance targets and examined State-wide safeguard performance. This paper represents the most recent iteration of LANL’s SLA development approach and the assessment of its applicability to the IAEA’s State-level Concept

A RNA-Seq Analysis of the Rat Supraoptic Nucleus Transcriptome: Effects of Salt Loading on Gene Expression

<div><p>Magnocellular neurons (MCNs) in the hypothalamo-neurohypophysial system (HNS) are highly specialized to release large amounts of arginine vasopressin (Avp) or oxytocin (Oxt) into the blood stream and play critical roles in the regulation of body fluid homeostasis. The MCNs are osmosensory neurons and are excited by exposure to hypertonic solutions and inhibited by hypotonic solutions. The MCNs respond to systemic hypertonic and hypotonic stimulation with large changes in the expression of their Avp and Oxt genes, and microarray studies have shown that these osmotic perturbations also cause large changes in global gene expression in the HNS. In this paper, we examine gene expression in the rat supraoptic nucleus (SON) under normosmotic and chronic salt-loading SL) conditions by the first time using “new-generation”, RNA sequencing (RNA-Seq) methods. We reliably detect 9,709 genes as present in the SON by RNA-Seq, and 552 of these genes were changed in expression as a result of chronic SL. These genes reflect diverse functions, and 42 of these are involved in either transcriptional or translational processes. In addition, we compare the SON transcriptomes resolved by RNA-Seq methods with the SON transcriptomes determined by Affymetrix microarray methods in rats under the same osmotic conditions, and find that there are 6,466 genes present in the SON that are represented in both data sets, although 1,040 of the expressed genes were found only in the microarray data, and 2,762 of the expressed genes are selectively found in the RNA-Seq data and not the microarray data. These data provide the research community a comprehensive view of the transcriptome in the SON under normosmotic conditions and the changes in specific gene expression evoked by salt loading.</p></div

Transcriptional and Translational Regulator mRNAs increased in expression by SL.

<p>^aMean Control and Mean SL data are averages of three samples each and are expressed in quantile (log2 (RPKM+2)) units.</p><p>Transcriptional and Translational Regulator mRNAs increased in expression by SL.</p

Transcriptional and Translational Regulator mRNAs decreased in expression by SL.

<p>^aMean Control and Mean SL data are averages of three samples each and are expressed in quantile (log2 (RPKM+2)) units.</p><p>Transcriptional and Translational Regulator mRNAs decreased in expression by SL.</p