Miracle-dz/UniFAR-FTUs huggingface dataset:
Cutting Edge: Generation of Effector Cells That Localize to Mucosal Tissues and Form Resident Memory CD8 T Cells Is Controlled by mTOR

Mucosal tissues are subject to frequent pathogen exposure and are major sites for transmission of infectious disease. CD8 T cells play a critical role in controlling mucosa-acquired infections even though their migration into mucosal tissues is tightly regulated. The mechanisms and signals that control the formation of tissue-resident memory CD8 T cells are poorly understood; however, one key regulator of memory CD8 T cell differentiation, mammalian target of rapamycin kinase, can be inhibited by rapamycin. We report that, despite enhancing the formation of memory CD8 T cells in secondary lymphoid tissues, rapamycin inhibits the formation of resident memory CD8 T cells in the intestinal and vaginal mucosa. The ability of rapamycin to block the formation of functional resident CD8 T cells in mucosal tissues protected mice from a model of CD8 T cell–mediated lethal intestinal autoimmunity. These findings demonstrate an opposing role for mammalian target of rapamycin in the formation of resident versus nonresident CD8 T cell immunity.
RECEPTORS FOR ATRIAL NATRIURETIC PEPTIDE ON ISOLATED RAT ADIPOCYTES

High specific binding sites for atrial natriuretic peptide (ANP; 99-126) on isolated rat adipocytes are reported in the present study. Binding of ANP to rat adipocytes was time» and temperature-dependent and proportional to the cell concentration. Analysis of the binding data by the method of Scatchard revealed a dissociation constant (Kd) of 2.32”; 0.39 nM. Peptides like glucagon (1 ,uM), gastric inhibitory peptide (l ,uM) and insulin (l ,uM) which were known to possess receptors on rat adipocytes were not able to displace ml-labelled ANP from the receptor. Binding of ANP resulted in an cGMP increase which was maximal after 2 min at 25°C. The cGMP production was stimulated concentration-dependently by ANP. “ Our findings suggest a possibleirole for ANP in fat metabolism. Atrial natriuretic peptides (ANPs) have been identified in various tissues including mammalian atrial myocytes (3) kidneys, adrenals, pituitary (15, l6), lungs (4) and intestine (22). ANP(99—]26), the carboxy terminal 28 amino acid residue of the ANP precursor (proANP: 1-I26), is considered to be the major physiologically active peptide of the ANPs (l9, 20). ANP exerts a wide spectrum of metabolic and cardiovascular effects (for review, see 25) and receptors for ANP have been identified in a wide variety of tissues including blood vessels (6, 17), cardiac tissue (5), lung (9), exocrine pancreas (2) and insulinoma-derived RINm5F cells (21). The present work was undertaken to examine the presence of receptors for ANP on isolated rat adipocytes mediating possible effects on fat metabolism. This is of interest since accumulating evidence suggests multiple effects of ANP in addition to the vvell-characterized actions on the cardiovascular system (25). MATERIALS AND METHODS
HDAC8-Mediated Epigenetic Reprogramming Plays a Key Role in Resistance to Anthrax Lethal Toxin–Induced Pyroptosis in Macrophages

Macrophages pre-exposed to a sublethal dose of anthrax lethal toxin (LeTx) are refractory to subsequent high cytolytic doses of LeTx, termed toxin-induced resistance (TIR). A small population of TIR cells (2–4%) retains TIR characteristics for up to 5–6 wk. Through studying these long-term TIR cells, we found that a high level of histone deacetylase (HDAC)8 expression was crucial for TIR. Knocking down or inhibition of HDAC8 by small interfering RNAs or the HDAC8-specific inhibitor PCI-34051, respectively, induced expression of the mitochondrial death genes Bcl2 adenovirus E1B 19 kDa–interacting protein 3 (BNIP3), BNIP3-like and metastatic lymph node 64, and resensitized TIR cells to LeTx. Among multiple histone acetylations, histone H3 lysine 27 (H3K27) acetylation was most significantly decreased in TIR cells in an HDAC8-dependent manner, and the association of H3K27 acetylation with the genomic regions of BNIP3 and metastatic lymph node 64, where HDAC8 was recruited to, was diminished in TIR cells. Furthermore, overexpression of HDAC8 or knocking down the histone acetyltransferase CREB-binding protein/p300, known to target H3K27, rendered wild-type cells resistant to LeTx. As in RAW264.7 cells, primary bone marrow–derived macrophages exposed to a sublethal dose of LeTx were resistant to LeTx in an HDAC8-dependent manner. Collectively, this study demonstrates that epigenetic reprogramming mediated by HDAC8 plays a key role in determining the susceptibility of LeTx-induced pyroptosis in macrophages.
Psychological factors determining success in a medical career: A 10-year longitudinal study

Background: Systemic review of predictors of success in medical career is an important tool to recognize the indicators of proper training. Aim: To determine psychological factors that predict success in a medical career. The success is defined as professional competence, satisfaction with medicine as a career, occupational stress and burnout and quality of life (QOF). Methods: Part I (1999–2005), medical students were examined each subsequent year, beginning with admission. Assessment included academic achievement (high school final examination results, entrance exam results, academic results during medical school) and psychological characteristics (sense of coherence (SOC), depression, anxiety, coping styles, value system and need for social approval). Part II (2008–2009), the same participants completed an Internet survey 4 years after graduation. Results of the postgraduate medical exam were taken under consideration. Results: Academic achievement predicts only professional competence. Coping styles are significant indicators of satisfaction with medicine as a career. SOC, while assessed with anxiety and depression during studies, enabled us to recognize future QOF of medical graduates. Professional stress is not predictable to such an extent as other success indicators. Conclusions: There are significant psychological qualities useful to draw the outline of the future job and life performance of medical graduates.
Set7 Facilitates Hepatitis C Virus Replication via Enzymatic Activity–Dependent Attenuation of the IFN-Related Pathway

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, usually resulting in persistent infection involving hepatic steatosis, cirrhosis, and hepatocellular carcinoma via escape of the host’s immune response. Set7 is a lysine-specific methyltransferase that is involved in gene regulation and virus replication. However, the mechanism underlying the immune evasion between HCV and Set7 is not well understood. In this study, we observed that the expression of Set7 in Huh7.5. 1 cells was upregulated by HCV infection, and high levels of Set7 expression were also found in the sera, PBMCs, and liver tissue of HCV patients relative to healthy individuals. Further investigation showed that Set7 enhanced HCV replication in an enzymatic activity–dependent manner. Moreover, our data showed that Set7 decreased the expression of virus-induced IFN and IFN-related effectors, such as dsRNA-activated protein kinase and 2′,5′-oligoadenylate synthetase. Further investigation suggested that Set7 suppressed the endogenous IFN expression by reducing the nuclear translocation of IFN regulatory factor 3/7 and the p65 subunit of NF-κB and reduced IFN-induced dsRNA-activated protein kinase and 2′,5′-oligoadenylate synthetase via attenuation of the phosphorylation of STAT1 and STAT2. Additionally, IFN receptors, including IFNAR1 and IFNAR2, which are located upstream of the JAK/STAT pathway, were reduced by Set7. Taken together, our results reveal that Set7 facilitates HCV replication through the attenuation of IFN signaling pathways and IFN-related effectors.
Transcription-Dependent Generation of a Specialized Chromatin Structure at the TCRβ Locus

V(D)J recombination assembles Ag receptor genes during lymphocyte development. Enhancers at AR loci are known to control V(D)J recombination at associated alleles, in part by increasing chromatin accessibility of the locus, to allow the recombination machinery to gain access to its chromosomal substrates. However, whether there is a specific mechanism to induce chromatin accessibility at AR loci is still unclear. In this article, we highlight a specialized epigenetic marking characterized by high and extended H3K4me3 levels throughout the Dβ-Jβ-Cβ gene segments. We show that extended H3K4 trimethylation at the Tcrb locus depends on RNA polymerase II (Pol II)–mediated transcription. Furthermore, we found that the genomic regions encompassing the two DJCβ clusters are highly enriched for Ser5-phosphorylated Pol II and short-RNA transcripts, two hallmarks of transcription initiation and early transcription. Of interest, these features are shared with few other tissue-specific genes. We propose that the entire DJCβ regions behave as transcription “initiation” platforms, therefore linking a specialized mechanism of Pol II transcription with extended H3K4 trimethylation and highly accessible Dβ and Jβ gene segments.
Elderly Patients’ Experiences of Meeting With the Doctor

Previous research has provided contradictory findings on how important it is for elderly patients to actively participate in the meeting with their doctors. Using descriptive and exploratory interview study with 20 elderly patients discharged from medicine and geriatric hospital care in Sweden, the authors describe how elderly patients experience their meetings with their doctor in the hospital setting. The results indicate that the meetings between elderly patients and doctors are influenced by the nature and shape of the conversation, which are influenced by power and interaction. A good relationship between an elderly patient and his or her doctor leads to reduced apprehension and increased faith in the health care system. This study was inspired by the sociocultural perspective and highlights the importance of the health care sector becoming a learning organization in which doctors are trained to prevent misunderstandings in their meetings with elderly patients.
The microRNA Biogenesis Machinery Modulates Lineage Commitment during αβ T Cell Development

Differentiation of CD4+ helper and CD8+ cytotoxic αβ T cells from CD4+CD8+ thymocytes involves upregulation of lineage-specifying transcription factors and transcriptional silencing of CD8 or CD4 coreceptors, respectively, in MHC class II or I (MHCII or I)–restricted thymocytes. In this study, we demonstrate that inactivation of the Dicer RNA endonuclease in murine thymocytes impairs initiation of Cd4 and Cd8 silencing, leading to development of positively selected MHCI- and MHCII-restricted mature CD4+CD8+ thymocytes. Expression of the antiapoptotic BCL2 protein or inactivation of the p53 proapoptotic protein rescues these thymocytes from apoptosis, increasing their frequency and permitting accumulation of CD4+CD8+ αβ T cells in the periphery. Dicer-deficient MHCI-restricted αβ T cells fail to normally silence Cd4 and display impaired induction of the CD8 lineage–specifying transcription factor Runx3, whereas Dicer-deficient MHCII-restricted αβ T cells show impaired Cd8 silencing and impaired induction of the CD4 lineage–specifying transcription factor Thpok. Finally, we show that the Drosha RNA endonuclease, which functions upstream of Dicer in microRNA biogenesis, also regulates Cd4 and Cd8 silencing. Our data demonstrate a previously dismissed function for the microRNA biogenesis machinery in regulating expression of lineage-specifying transcription factors and silencing of Cd4 and Cd8 during αβ T cell differentiation.
Does Knowledge Base Compatibility Help or Hurt Knowledge Sharing between Suppliers in Coopetition? the Role of Customer Participation

Competing suppliers that collaborate to serve downstream original equipment manufacturer customers often encounter partners with overlapping and compatible knowledge bases. Such knowledge base compatibility provides supplier partners the opportunity to exchange knowledge efficiently, leading to greater knowledge sharing. However, the ease of misappropriation of the shared knowledge can offset this beneficial effect. This research proposes that the effect of knowledge base compatibility on supplier partners' knowledge sharing is moderated by the customer's participation in the collaborative effort and by the customer value such effort creates. The results of two empirical studies show that when levels of both customer participation and customer value are high, knowledge base compatibility between supplier partners leads to greater knowledge sharing. In contrast, when customer participation is high but customer value is low, knowledge base compatibility leads to lower levels of supplier knowledge sharing. This investigation validates the importance of key factors related to supplier partners' opportunity and motivation to share knowledge in coopetitive partnerships.
Properdin Contributes to Allergic Airway Inflammation through Local C3a Generation

Complement is implicated in asthma pathogenesis, but its mechanism of action in this disease remains incompletely understood. In this study, we investigated the role of properdin (P), a positive alternative pathway complement regulator, in allergen-induced airway inflammation. Allergen challenge stimulated P release into the airways of asthmatic patients, and P levels positively correlated with proinflammatory cytokines in human bronchoalveolar lavage (BAL). High levels of P were also detected in the BAL of OVA-sensitized and challenged but not naive mice. Compared with wild-type (WT) mice, P-deficient (P−/−) mice had markedly reduced total and eosinophil cell counts in BAL and significantly attenuated airway hyperresponsiveness to methacholine. Ab blocking of P at both sensitization and challenge phases or at challenge phase alone, but not at sensitization phase alone, reduced airway inflammation. Conversely, intranasal reconstitution of P to P−/− mice at the challenge phase restored airway inflammation to wild-type levels. Notably, C3a levels in the BAL of OVA-challenged P−/− mice were significantly lower than in wild-type mice, and intranasal coadministration of an anti-C3a mAb with P to P−/− mice prevented restoration of airway inflammation. These results show that P plays a key role in allergen-induced airway inflammation and represents a potential therapeutic target for human asthma.
Cutting Edge: STING Mediates Protection against Colorectal Tumorigenesis by Governing the Magnitude of Intestinal Inflammation

Stimulator of IFN genes (STING) is a cytoplasmic innate immune sensor for cyclic dinucleotides that also serves a dual role as an adaptor molecule for a number of intracellular DNA receptors. Although STING has important functions in the host defense against pathogens and autoimmune diseases, its physiological role in cancer is unknown. In this study, we show that STING-deficient mice are highly susceptible to colitis-associated colorectal cancer. Colons of STING-deficient mice exhibit significant intestinal damage and overt proliferation during early stages of tumorigenesis. Moreover, STING-deficient mice fail to restrict activation of the NF-κB– and STAT3-signaling pathways, which leads to increased levels of the proinflammatory cytokines IL-6 and KC. Therefore, our results identified an unexpected and important role for STING in mediating protection against colorectal tumorigenesis.
CHD Prevalence in Americans Age 50 Years and Older Using NCEP and WHO Definitions of Metabolic Syndrome

The World Health Organization (WHO) criteria for metabolic syndrome were originally published in 1998 and subsequently revised in 1999. The National Cholesterol Education Program (NCEP) proposed somewhat different criteria for the metabolic syndrome in 2001. This study compares the NCEP and WHO criteria for metabolic syndrome with respect to prevalence of coronary heart disease (CHD) in those 50 years and older. The Third National Health and Nutrition Examination Survey (NHANES III) was used to classify adults (> 50 years) by metabolic syndrome using NCEP and 1999 WHO definitions. Risk factor information for components of the metabolic syndrome, traditional cardiovascular risk factors and the prevalence of CHD were determined for each group. Individuals 50 years and older meeting only NCEP criteria had more traditional cardiovascular risk factors than those only meeting WHO criteria and less insulin resistance, per se. Consequently, the NCEP‐only group had a greater prevalence of CHD (18.8%) compared to the WHO‐only group (12.6%, p < 0.001). As a whole (including all individuals who met either NCEP or WHO criteria), prevalence of CHD was significantly higher in those meeting the NCEP definition (15.5%) compared to those meeting the WHO definition of metabolic syndrome (14.1%, p < 0.001). In conclusion, many individuals 50 years and older meet both NCEP and WHO criteria for metabolic syndrome (i.e., there is substantial concordance between the two criteria) and both criteria identify individuals with insulin resistance. NCEP criteria identified individuals with significantly higher CHD prevalence compared to the WHO criteria. In spite of the fact that individuals who met only the WHO criteria were more insulin resistant than the NCEP‐only individuals, those who met only the NCEP clinical criteria for metabolic syndrome had a much worse cardiovascular risk profile and were more likely to have prevalent CHD than those who met only the WHO criteria.
Cutting Edge: New Chimeric NOD2/TLR2 Adjuvant Drastically Increases Vaccine Immunogenicity

TLR ligands are critical activators of innate immunity and are being developed as vaccine adjuvants. However, their usefulness in conjunction with NOD-like receptor agonists remains poorly studied. In this study, we evaluated a new ligand that targets both TLR2 and NOD2 receptors. We assessed its ability to enhance dendritic cell maturation in vitro in addition to improving systemic and mucosal immune responses in mice. The chimeric NOD2/TLR2 ligand induced synergistic upregulation of dendritic cell maturation markers, costimulatory molecules, and secretion of proinflammatory cytokines compared with combinations of separate ligands. Furthermore, when coadministered with biodegradable nanoparticles carrying a model Ag, the ligand was able to induce high Ag-specific IgA and IgG titers at both systemic and mucosal sites after parenteral immunizations. These findings point out the potential utility of chimeric molecules TLR/NOD as adjuvants for vaccines to induce systemic and mucosal immune responses.
IgG-Immune Complexes Promote B Cell Memory by Inducing BAFF

Memory B cell responses are vital for protection against infections but must also be regulated to prevent autoimmunity. Cognate T cell help, somatic hypermutation, and affinity maturation within germinal centers (GCs) are required for high-affinity memory B cell formation; however, the signals that commit GC B cells to the memory pool remain unclear. In this study, we identify a role for IgG-immune complexes (ICs), FcγRs, and BAFF during the formation of memory B cells in mice. We found that early secretion of IgG in response to immunization with a T-dependent Ag leads to IC–FcγR interactions that induce dendritic cells to secrete BAFF, which acts at or upstream of Bcl-6 in activated B cells. Loss of CD16, hematopoietic cell–derived BAFF, or blocking IC:FcγR regions in vivo diminished the expression of Bcl-6, the frequency of GC and memory B cells, and secondary Ab responses. BAFF also contributed to the maintenance and/or expansion of the follicular helper T cell population, although it was dispensable for their formation. Thus, early Ab responses contribute to the optimal formation of B cell memory through IgG-ICs and BAFF. Our work defines a new role for FcγRs in GC and memory B cell responses.
Identification of a Novel Splice Variant Isoform of TREM-1 in Human Neutrophil Granules

Triggering receptor expressed on myeloid cells-1 (TREM-1) is critical for inflammatory signal amplification. Humans have two forms of TREM-1: a membrane receptor, associated with the adaptor DAP12, and a soluble receptor detected at times of infection. The membrane receptor isoform acts synergistically with the TLR pathway to promote cytokine secretion and neutrophil migration, whereas the soluble receptor functions as a counterregulatory molecule. In multiple models of sepsis, exogenous administration of soluble forms of TREM-1 attenuates inflammation and markedly improves survival. Despite intense interest in soluble TREM-1, both as a clinical predictor of survival and as a therapeutic tool, the origin of native soluble TREM-1 remains controversial. Using human neutrophils, we identified a 15-kDa TREM-1 isoform in primary (azurophilic) and secondary (specific) granules. Mass spectrometric analysis, ELISA, and immunoblot confirm that the 15-kDa protein is a novel splice variant form of TREM-1 (TREM-1sv). Neutrophil stimulation with Pseudomonas aeruginosa, LPS, or PAM(3)Cys4 resulted in degranulation and release of TREM-1sv. The addition of exogenous TREM-1sv inhibited TREM-1 receptor–mediated proinflammatory cytokine production. Thus, these data reveal that TREM-1 isoforms simultaneously activate and inhibit inflammation via the canonical membrane TREM-1 molecule and this newly discovered granular isoform, TREM-1sv.
Casein Kinase II Controls TBK1/IRF3 Activation in IFN Response against Viral Infection

By sensing viral nucleic acids, host innate receptors elicit signaling pathways converging on TBK1-IFN regulatory factor (IRF)3 axis in mediating IFN-αβ induction and defense mechanisms. In contrast, viruses have evolved with diverse immune evasion/interference mechanisms to undermine innate receptor signaling and IFN response. In this regard, approaches enabling host to overcome such immune evasion/interference mechanisms are urgently needed to combat infections by epidemic/pandemic viruses. In this study, we report that protein kinase CK2 serves as a key component controlling TBK1 and IRF3 activation in IFN-inducing TLR, RIG-I–like receptors, and cGAS/STING signaling pathways. Accordingly, knocking down of CK2 expression or genetic ablation of its kinase activity resulted in elevated IFN-αβ response in response to infection by DNA and RNA viruses. Moreover, PP2A was identified as one of the intermediate phosphatases responsible for CK2-regulated IFN response, suggesting that CK2 may regulate TBK1 and IRF3 activation indirectly. Importantly, blockade of CK2 activity by small molecule inhibitor was able to activate TBK1, whereby eliciting effective host defense mechanisms against hepatitis C virus infection. Taken together, our results identify CK2 as a novel regulator of TBK1 and IRF3 and suggest that targeting CK2 by small molecular inhibitor may be a viable approach to prevent and treat viral infections.