On the role of the inhibitory receptor LAG-3 in acute and chronic LCMV infection

Chronic viral infections are often characterized by CD8 T-cell responses with poor cytokine secretion potential and limited expansion of the CD8 T-cell pool, collectively referred to as CD8 T-cell exhaustion. Exhaustion of lymphocytic choriomeningitis virus (LCMV)-specific CD8 T cells was shown to be partially regulated by the inhibitory receptor programmed death 1 (PD-1). Here, we demonstrate that exhausted LCMV-specific CD8 T cells also express the negative regulatory receptor lymphocyte activation gene 3 (LAG-3) which is mainly expressed on cells co-expressing the negative regulatory receptors PD-1 and Tim-3. Expression levels of LAG-3 on anti-viral CD8 T cells remain stable over short-term in vitro stimulations in presence of antigenic peptide. Nevertheless, in vitro and in vivo blockade of LAG-3 did not rescue cytokine production by virus-specific CD8 T cells and did not alter the virus titer in various organs. Likewise, chronic LCMV infection of LAG-3−/− mice led to a comparable degree of T-cell exhaustion as observed in C57BL/6 controls and to similar virus titers. Further, LAG-3 did not influence T-cell activation or cell division during chronic LCMV infection. These data suggest that even though LAG-3 is continuously up-regulated on LCMV-specific exhausted CD8 T cells, it alone does not significantly contribute to T-cell exhaustio

Estimating the in vivo killing efficacy of cytotoxic T lymphocytes across different peptide-MHC complex densities

Cytotoxic T lymphocytes (CTLs) are important agents in the control of intracellular pathogens, which specifically recognize and kill infected cells. Recently developed experimental methods allow the estimation of the CTL's efficacy in detecting and clearing infected host cells. One method, the in vivo killing assay, utilizes the adoptive transfer of antigen displaying target cells into the bloodstream of mice. Surprisingly, killing efficacies measured by this method are often much higher than estimates obtained by other methods based on, for instance, the dynamics of escape mutations. In this study, we investigated what fraction of this variation can be explained by differences in peptide loads employed in in vivo killing assays. We addressed this question in mice immunized with lymphocytic choriomeningitis virus (LCMV). We conducted in vivo killing assays varying the loads of the immunodominant epitope GP33 on target cells. Using a mathematical model, we determined the efficacy of effector and memory CTL, as well as CTL in chronically infected mice. We found that the killing efficacy is substantially reduced at lower peptide loads. For physiological peptide loads, our analysis predicts more than a factor 10 lower CTL efficacies than at maximum peptide loads. Assuming that the efficacy scales linearly with the frequency of CTL, a clear hierarchy emerges among the groups across all peptide antigen concentrations. The group of mice with chronic LCMV infections shows a consistently higher killing efficacy per CTL than the acutely infected mouse group, which in turn has a consistently larger efficacy than the memory mouse group. We conclude that CTL killing efficacy dependence on surface epitope frequencies can only partially explain the variation in in vivo killing efficacy estimates across experimental methods and viral systems, which vary about four orders of magnitude. In contrast, peptide load differences can explain at most two orders of magnitude

GNO Solar Neutrino Observations: Results for GNOI

We report the first GNO solar neutrino results for the measuring period GNOI, solar exposure time May 20, 1998 till January 12, 2000. In the present analysis, counting results for solar runs SR1 - SR19 were used till April 4, 2000. With counting completed for all but the last 3 runs (SR17 - SR19), the GNO I result is [65.8 +10.2 -9.6 (stat.) +3.4 -3.6 (syst.)]SNU (1sigma) or [65.8 + 10.7 -10.2 (incl. syst.)]SNU (1sigma) with errors combined. This may be compared to the result for Gallex(I-IV), which is [77.5 +7.6 -7.8 (incl. syst.)] SNU (1sigma). A combined result from both GNOI and Gallex(I-IV) together is [74.1 + 6.7 -6.8 (incl. syst.)] SNU (1sigma).Comment: submitted to Physics Letters B, June 2000. PACS: 26.65. +t ; 14.60 Pq. Corresponding author: [email protected] ; [email protected]

Humans in XAI: increased reliance in decision-making under uncertainty by using explanation strategies

IntroductionAlthough decision support systems (DSS) that rely on artificial intelligence (AI) increasingly provide explanations to computer and data scientists about opaque features of the decision process, especially when it involves uncertainty, there is still only limited attention to making the process transparent to end users.MethodsThis paper compares four distinct explanation strategies employed by a DSS, represented by the social agent Floka, designed to assist end users in making decisions under uncertainty. Using an economic experiment with 742 participants who make lottery choices according to the Holt and Laury paradigm, we contrast two explanation strategies offering accurate information (transparent vs. guided) with two strategies prioritizing human-centered explanations (emotional vs. authoritarian) and a baseline (no explanation).Results and discussionOur findings indicate that a guided explanation strategy results in higher user reliance than a transparent strategy. Furthermore, our results suggest that user reliance is contingent on the chosen explanation strategy, and, in some instances, the absence of an explanation can also lead to increased user reliance

Complete results for five years of GNO solar neutrino observations

We report the complete GNO solar neutrino results for the measuring periods GNO III, GNO II, and GNO I. The result for GNO III (last 15 solar runs) is [54.3 + 9.9 - 9.3 (stat.)+- 2.3 (syst.)] SNU (1 sigma) or [54.3 + 10.2 - 9.6 (incl. syst.)] SNU (1 sigma) with errors combined. The GNO experiment is now terminated after altogether 58 solar exposure runs that were performed between May 20, 1998 and April 9, 2003. The combined result for GNO (I+II+III) is [62.9 + 5.5 - 5.3 (stat.) +- 2.5 (syst.)] SNU (1 sigma) or [62.9 + 6.0 - 5.9] SNU (1 sigma) with errors combined in quadrature. Overall, gallium based solar observations at LNGS (first in GALLEX, later in GNO) lasted from May 14, 1991 through April 9, 2003. The joint result from 123 runs in GNO and GALLEX is [69.3 +- 5.5 (incl. syst.)] SNU (1 sigma). The distribution of the individual run results is consistent with the hypothesis of a neutrino flux that is constant in time. Implications from the data in particle- and astrophysics are reiterated.Comment: 22 pages incl. 9 Figures and 8 Tables. to appear in: Physics Letters B (accepted April 13, 2005) PACS: 26.65.+t ; 14.60.P

HDMX-L is expressed from a functional P53-responsive promoter in the first intron of the HDMX gene, and participates in an auto-regulatory feedback loop to control P53 activity.

The p53 regulatory network is critically involved in preventing the initiation of cancer. In unstressed cells p53 is maintained at low levels and is largely inactive, mainly through the action of its two essential negative regulators, HDM2 and HDMX. p53 abundance and activity are upregulated in response to various stresses including DNA damage and oncogene activation. Active p53 initiates transcriptional and transcription-independent programs that result in cell cycle arrest, cellular senescence or apoptosis. p53 also activates transcription of HDM2, which initially leads to the degradation of HDMX, creating a positive feedback loop to obtain maximal activation of p53. Subsequently, when stress-induced post-translational modifications start to decline, HDM2 becomes effective in targeting p53 for degradation, thus attenuating the p53 response. To date, no clear function for HDMX in this critical attenuation phase has been demonstrated experimentally. Like HDM2, the HDMX gene contains a promoter (P2) in its first intron that is potentially inducible by p53. We show that p53 activation in response to a plethora of p53-activating agents induces the transcription of a novel HDMX mRNA transcript from the HDMX-P2 promoter. This mRNA is more efficiently translated than that expressed from the constitutive HDMX-P1 promoter, and it encodes a long form of HDMX protein, HDMX-L. Importantly, we demonstrate that HDMX-L cooperates with HDM2 to promote the ubiquitination of p53, and that p53-induced HDMX transcription from the P2 promoter can play a key role in the attenuation phase of the p53-response, to effectively diminish p53 abundance as cells recover from stress

Environmental considerations and current status of grouping and regulation of engineered nanomaterials

This article reviews the current status of nanotechnology with emphasis on application and related environmental considerations as well as legislation. Application and analysis of nanomaterials in infrastructure (construction, building coatings, and water treatment) is discussed, and in particular nanomaterial release during the lifecycle of these applications. Moreover, possible grouping approaches with regard to ecotoxicological and toxicological properties, and the fate of nanomaterials in the environment are evaluated. In terms of potential exposure, the opportunities that arise from leveraging advances in several key areas, such as water treatment and construction are addressed. Additionally, this review describes challenges with regard to the European Commission’s definition of ‘nanomaterial’. The revised REACH information requirements, intended to enable a comprehensive risk assessment of nanomaterials, are outlined

Analytical and toxicological aspects of nanomaterials in different product groups: Challenges and opportunities

The widespread integration of engineered nanomaterials into consumer and industrial products creates new challenges and requires innovative approaches in terms of design, testing, reliability, and safety of nanotechnology. The aim of this review article is to give an overview of different product groups in which nanomaterials are present and outline their safety aspects for consumers. Here, release of nanomaterials and related analytical challenges and solutions as well as toxicological considerations, such as dose-metrics, are discussed. Additionally, the utilization of engineered nanomaterials as pharmaceuticals or nutraceuticals to deliver and release cargo molecules is covered. Furthermore, critical pathways for human exposure to nanomaterials, namely inhalation and ingestion, are discussed in the context of risk assessment. Analysis of NMs in food, innovative medicine or food contact materials is discussed. Specific focus is on the presence and release of nanomaterials, including whether nanomaterials can migrate from polymer nanocomposites used in food contact materials. With regard to the toxicology and toxicokinetics of nanomaterials, aspects of dose metrics of inhalation toxicity as well as ingestion toxicology and comparison between in vitro and in vivo conclusions are considered. The definition of dose descriptors to be applied in toxicological testing is emphasized. In relation to potential exposure from different products, opportunities arising from the use of advanced analytical techniques in more unique scenarios such as release of nanomaterials from medical devices such as orthopedic implants are addressed. Alongside higher product performance and complexity, further challenges regarding material characterization and safety, as well as acceptance by the general public are expected