655 research outputs found
Antigen-activated human T lymphocytes express cell-surface NKG2D ligands via an ATM/ATR-dependent mechanism and become susceptible to autologous NK-cell lysis
No full textRecent evidence indicates that natural killer (NK) cells can negatively regulate T-cell responses, but the mechanisms behind this phenomenon as a consequence of NK-T-cell interactions are poorly understood. We studied the interaction between the NKG2D receptor and its ligands (NKG2DLs), and asked whether T cells expressed NKG2DLs in response to superantigen, alloantigen, or a specific antigenic peptide, and if this rendered them susceptible to NK lysis. As evaluated by FACS, the major histocompatibility complex (MHC) class I chain-related protein A (MICA) was the ligand expressed earlier on both CD4(+) and CD8(+) T cells in 90% of the donors tested, while UL16-binding protein-1 (ULBP)1, ULBP2, and ULBP3 were induced at later times in 55%-75% of the donors. By carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling, we observed that NKG2DLs were expressed mainly on T cells that had gone through at least one division. Real-time reverse-transcription polymerase chain reaction confirmed the expression of all NKG2DLs, except ULBP4. In addition, T-cell activation stimulated phosphorylation of ataxia-telangiectasia mutated (ATM), a kinase required for NKG2DLs expression after DNA damage, and ATM/Rad3-related kinase (ATR) inhibitors blocked MICA induction on T cells with a mechanism involving NF-kappaB. Finally, we demonstrated that activated T cells became susceptible to autologous NK lysis via NKG2D/NKG2DLs interaction and granule exocytosis, suggesting that NK lysis of T lymphocytes via NKG2D may be an additional mechanism to limit T-cell responses
DNAM-1 ligand expression on Ag-stimulated T lymphocytes is mediated by ROS-dependent activation of DNA-damage response: relevance for NK-T cell interaction
No full textAn important role for natural killer (NK) cells in the regulation of T-cell responses is emerging, although the receptor pairs regulating the NK-T-cell interaction have still not been identified. We found that superantigen-stimulated T cells express Nectin-2 (CD112) and poliovirus receptor (PVR; CD155), the ligands of the activating NK receptor DNAX accessory molecule-1 (DNAM-1; CD226). Interestingly, only PVR was present at the T cell surface, particularly on cells in the S and G(2)/M phases of the cell cycle. The up-regulation of PVR expression involves DNA-damage response (DDR)-dependent pathways, because we found that pharmacologic inhibition of ATM and ATR kinases reduced PVR expression and that PVR was almost exclusively induced on cells expressing the DDR marker gamma H2AX. Oxidative stress contributed to DDR activation, and our results showed impaired PVR levels in the presence of the reactive oxygen species (ROS) scavenger N-acetyl-cysteine (NAC), being monocytes the main ROS source needed for optimal PVR expression on activated T cells. Interestingly, in accordance with ligand expression, NK cells lysed allogeneic proliferating more efficiently than nonproliferating T lymphocytes, with a mechanism requiring the cooperation between DNAM-1 and NKG2D. These results could contribute to unraveling the role of NK cells in the down-regulation of T-cell responses in physiologic and pathologic processes such as autoimmunity or GVHD. (Blood. 2011; 117(18): 4778-4786
Src-dependent Syk activation controls CD69-mediated signaling and function on human NK cells
No full textCD69 C-type lectin receptor represents a functional triggering molecule on activated NK cells, capable of directing their natural killing function. The receptor-proximal signaling pathways activated by CD69 cross-linking and involved in CD69-mediated cytotoxic activity are still poorly understood. Here we show that CD69 engagement leads to the rapid and selective activation of the tyrosine kinase Syk, but not of the closely related member of the same family, ZAP70, in IL-2-activated human NK cells. Our results indicate the requirement for Src family kinases in the CD69-triggered activation of Syk and suggest a role for Lek in this event. We also demonstrate that Syk and Src family tyrosine kinases control the CD69-triggered tyrosine phosphorylation and activation of phospholipase Cgamma2 and the Rho family-specific exchange factor Vav1 and are responsible for CD69-triggered cytotoxicity of activated NK cells. The same CD69-activated signaling pathways are also observed in an RBL transfectant clone, constitutively expressing the receptor. These data demonstrate for the first time that the CD69 receptor functionally couples to the activation of Src family tyrosine kinases, which, by inducing Syk activation, initiate downstream signaling pathways and regulate CD69-triggered functions on human NK cells
Disequilibrium in Gender Ratios among Authors who Contributed Equally
No full textAbstractIn recent decades, the biomedical literature has witnessed an increasing number of authors per article together with a concomitant increase of authors claiming to have contributed equally. In this study, we analyzed over 3000 publications from 1995–2017 claiming equal contributions for authors sharing the first author position for author number, gender, and gender position. The frequency of dual pairings contributing equally was male-male > mixed gender > female-female. For mixed gender pairs males were more often at the first position although the disparity has lessened in the past decade. Among author associations claiming equal contribution and containing three or more individuals, males predominated in both the first position and number of gender exclusive groupings. Our results show a disequilibrium in gender ratios among authors who contributed equally from expected ratios had the ordering been done randomly or alphabetical. Given the importance of the first author position in assigning credit for a publication, the finding of fewer than expected females in associations involving shared contributions raises concerns about women not receiving their fair share of expected credit. The results suggest a need for journals to request clarity on the method used to decide author order among individuals claiming to have made equal contributions to a scientific publication.</jats:p
Distinct Roles for Human Cytomegalovirus Immediate Early Proteins IE1 and IE2 in the Transcriptional Regulation of MICA and PVR/CD155 Expression
No full textElimination of virus-infected cells by cytotoxic lymphocytes is triggered by activating receptors, among which NKG2D and DNAM-1/CD226 play an important role. Their ligands, that is, MHC class I-related chain (MIC) A/B and UL16-binding proteins (ULBP)1-6 (NKG2D ligand), Nectin-2/CD112, and poliovirus receptor (PVR)/CD155 (DNAM-1 ligand), are often induced on virus-infected cells, although some viruses, including human CMV (HCMV), can block their expression. In this study, we report that infection of different cell types with laboratory or low-passage HCMV strains upregulated MICA, ULBP3, and PVR, with NKG2D and DNAM-1 playing a role in NK cell-mediated lysis of infected cells. Inhibition of viral DNA replication with phosphonoformic acid did not prevent ligand upregulation, thus indicating that early phases of HCMV infection are involved in ligand increase. Indeed, the major immediate early (IE) proteins IE1 and IE2 stimulated the expression of MICA and PVR, but not ULBP3. IE2 directly activated MICA promoter via its binding to an IE2-responsive element that we identified within the promoter and that is conserved among different alleles of MICA. Both IE proteins were instead required for PVR upregulation via a mechanism independent of IE DNA binding activity. Finally, inhibiting IE protein expression during HCMV infection confirmed their involvement in ligand increase. We also investigated the contribution of the DNA damage response, a pathway activated by HCMV and implicated in ligand regulation. However, silencing of ataxia telangiectasia mutated, ataxia telangiectasia and Rad3-related protein, and DNA-dependent protein kinase did not influence ligand expression. Overall, these data reveal that MICA and PVR are directly regulated by HCMV IE proteins, and this may be crucial for the onset of an early host antiviral response
all authors contributed equally Corresponding Author:
No full textBackground: Medical blogs have emerged as new media, extending to a wider range of medical audiences, including health professionals and patients to share health-related information. However, extraction of quality health-related information from medical blogs is challenging primarily because these blogs lack systematic methods to organize their posts. Medical blogs can be categorized according to their author into (1) physician-written blogs, (2) nurse-written blogs, and (3) patient-written blogs. This study focuses on how to organize physician-written blog posts that discuss disease-related issues and how to extract quality information from these posts. Objective: The goal of this study was to create and implement a prototype for a Web-based system, called ICDTag, based on a hybrid taxonomy–folksonomy approach that follows a combination of a taxonomy classification schemes and user-generated tags to organize physician-written blog posts and extract information from these posts. Methods: First, the design specifications for the Web-based system were identified. This system included two modules: (1) a blogging module that was implemented as one or more blogs, and (2) an aggregator module that aggregated posts from different blogs into an aggregator website. We then developed a prototype for this system in which the blogging module included two blogs, the cardiology blog and the gastroenterology blog. To analyze the usage patterns of the prototype, we conducted an experiment with data provided by cardiologists and gastroenterologists. Next, we conducted two evaluation types: (1) an evaluatio
Contributed equally
No full textFollowing publication of our recent article [1], we noticed an error in Figure 4. In part (e), the SLEDAI score for the frequency of CD4+ T cells expressing CCR4 and/or CCR6 in a patient with SLE at the times of low disease activities should be “6”, rather than “4”. The corrected Figure 4 is given here overleaf as Figure 1. Author detail
Attenuation of species abundance distributions by sampling
No full textQuantifying biodiversity aspects such as species presence/ absence, richness and abundance is an important challenge to answer scientific and resource management questions. In practice, biodiversity can only be assessed from biological material taken by surveys, a difficult task given limited time and resources. A type of random sampling, or often called sub-sampling, is a commonly used technique to reduce the amount of time and effort for investigating large quantities of biological samples. However, it is not immediately clear how (sub-)sampling affects the estimate of biodiversity aspects from a quantitative perspective. This paper specifies the effect of (sub-)sampling as attenuation of the species abundance distribution (SAD), and articulates how the sampling bias is induced to the SAD by random sampling. The framework presented also reveals some confusion in previous theoretical studies.Peer reviewe
Analysis of justification for author order and gender bias in author order among those contributing equally
No full textABSTRACTThe practice of designating two or more authors as equal contributors (ECs) on a scientific publication is increasingly common as a form of sharing credit. However, EC authors are often unclearly attributed on curriculum vitae (CVs) or citation engines, and it is unclear how research teams determine author order within an EC listing. In response to studies showing that male authors were more likely to be placed first in an EC listing, the American Society for Microbiology (ASM) required that authors explain the reasons for author order beginning in 2020. In this study, we analyze data from over 2,500 ASM publications to see how this policy affected gender bias and how research teams are making decisions on author order. Data on publications from 2018 to 2021 show that gender bias was largely nonsignificant both before and after authors were asked by ASM to provide an EC statement. The most likely reasons for EC order included alphabetical order, seniority, and chance, although there were differences for publications from different geographic regions. However, many research teams used unique methods in order selection, highlighting the importance of EC statements to provide clarity for readers, funding agencies, and tenure committees.IMPORTANCEFirst-author publications are important for early career scientists to secure funding and educational opportunities. However, an analysis published in eLife in 2019 noted that female authors are more likely to be placed second even when both authors report they have contributed equally. American Society for Microbiology announced in response that they would require submissions to include a written justification of author order. In this paper, we analyze the resultant data and show that laboratories are most likely to use some combination of alphabetical order, seniority, and chance to determine author order. However, the prevalence of these methods varies based on the research team's geographic location. These findings highlight the importance of equal contributor statements to provide clarity for readers, funding agencies, and tenure committees. Furthermore, this work is critically important for understanding how these decisions are made and provides a glimpse of the sociology of science
Genome sequence of Rhodobacter sphaeroides strain WS8N
No full textCopyright © 2011, American Society for MicrobiologyRhodobacter sphaeroides is a metabolically diverse photosynthetic alphaproteobacterium found ubiquitously in soil and freshwater habitats. Here we present the annotated genome sequence of R. sphaeroides WS8N.This research was funded by the UK Biotechnology and Biological Sciences Research Council
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