IL-6 selectively suppresses cDC1 specification via C/EBPβ

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in CDPs. Importantly, the ability of IL-6 to impair cDC development is dependent on the presence of C/EBPβ binding sites in the Zeb2 -165 kb enhancer, as this effect is lost in Δ1+2+3 mutant mice in which these binding sites are mutated. These results explain how tumor-associated IL-6 suppresses cDC1 development and suggest therapeutic approaches preventing abnormal C/EBPβ induction in CDPs may help reestablish cDC1 development to enhance antitumor immunity

Rubinstein-Taybi syndrome with scoliosis

<p>Abstract</p> <p>Study Design</p> <p>Case report.</p> <p>Objective</p> <p>The authors present the case of a 14-year-old boy with Rubinstein-Taybi syndrome (RSTS) presenting scoliosis.</p> <p>Summary of Background Data</p> <p>There have been no reports on surgery for RSTS presenting scoliosis.</p> <p>Methods</p> <p>The patient was referred to our hospital for evaluation of a progressive spinal curvature. A standing anteroposterior spine radiograph at presentation to our hospital revealed an 84-degree right thoracic curve from T6 to T12, along with a 63-degree left lumbar compensatory curve from T12 to L4. We planned a two-staged surgery and decided to fuse from T4 to L4. The first operation was front-back surgery because of the rigidity of the right thoracic curve. The second operation of lumbar anterior discectomy and fusion was arranged 9 months after the first surgery to prevent the crankshaft phenomenon due to his natural course of adolescent growth. To avoid respiratory complications, the patient was put on a respirator in the ICU for several days after both surgeries.</p> <p>Results</p> <p>Full-length spine radiographs after the first surgery revealed no instrumentation failure and showed that the right thoracic curve was corrected to 31 degrees and the left lumbar curve was corrected to 34 degrees. No postoperative complications occurred after both surgeries.</p> <p>Conclusions</p> <p>We succeeded in treating the patient without complications. Full-length spine standing radiographs at one year after the second operation demonstrated a stable bony arthrodesis with no loss of initial correction.</p

Monitoring the referral system through benchmarking in rural Niger: an evaluation of the functional relation between health centres and the district hospital

BACKGROUND: The main objective of this study is to establish a benchmark for referral rates in rural Niger so as to allow interpretation of routine referral data to assess the performance of the referral system in Niger. METHODS: Strict and controlled application of existing clinical decision trees in a sample of rural health centres allowed the estimation of the corresponding need for and characteristics of curative referrals in rural Niger. Compliance of referral was monitored as well. Need was matched against actual referral in 11 rural districts. The referral patterns were registered so as to get an idea on the types of pathology referred. RESULTS: The referral rate benchmark was set at 2.5 % of patients consulting at the health centre for curative reasons. Niger's rural districts have a referral rate of less than half this benchmark. Acceptability of referrals is low for the population and is adding to the deficient referral system in Niger. Mortality because of under-referral is highest among young children. CONCLUSION: Referral patterns show that the present programme approach to deliver health care leaves a large amount of unmet need for which only comprehensive first and second line health services can provide a proper answer. On the other hand, the benchmark suggests that well functioning health centres can take care of the vast majority of problems patients present with

T-cell and serological responses to Erp, an exported Mycobacterium tuberculosis protein, in tuberculosis patients and healthy individuals

<p>Abstract</p> <p>Background</p> <p>The identification of antigens able to differentiate tuberculosis (TB) disease from TB infection would be valuable. Cellular and humoral immune responses to Erp (Exported repetitive protein) – a recently identified <it>M. tuberculosis </it>protein – have not yet been investigated in humans and may contribute to this aim.</p> <p>Methods</p> <p>We analyzed the cellular and humoral immune responses to Erp, ESAT-6, Ag85B and PPD in TB patients, in BCG⁺individuals without infection, BCG⁺individuals with latent TB infection (LTBI) and BCG^-controls. We used lymphoproliferation, ELISpot IFN-γ, cytokine production assays and detection of specific human antibodies against recombinant <it>M. tuberculosis </it>proteins.</p> <p>Results</p> <p>We included 22 TB patients, 9 BCG⁺individuals without TB infection, 7 LTBI and 7 BCG^-controls. Erp-specific T cell counts were higher in LTBI than in the other groups. Erp-specific T cell counts were higher in LTBI subjects than TB patients (median positive frequency of 211 SFC/10⁶PBMC (range 118–2000) for LTBI subjects compared to 80 SFC/10⁶PBMC (range 50–191), p = 0.019); responses to PPD and ESAT-6 antigens did not differ between these groups. IFN-γ secretion after Erp stimulation differed between TB patients and LTBI subjects (p = 0.02). Moreover, LTBI subjects but not TB patients or healthy subjects produced IgG3 against Erp.</p> <p>Conclusion</p> <p>The frequencies of IFN-γ-producing specific T cells, the IFN-γ secretion and the production of IgG3 after Erp stimulation are higher in LTBI subjects than in TB patients, whereas PPD and ESAT-6 are not.</p

The CRE1 carbon catabolite repressor of the fungus Trichoderma reesei: a master regulator of carbon assimilation

<p>Abstract</p> <p>Background</p> <p>The identification and characterization of the transcriptional regulatory networks governing the physiology and adaptation of microbial cells is a key step in understanding their behaviour. One such wide-domain regulatory circuit, essential to all cells, is carbon catabolite repression (CCR): it allows the cell to prefer some carbon sources, whose assimilation is of high nutritional value, over less profitable ones. In lower multicellular fungi, the C2H2 zinc finger CreA/CRE1 protein has been shown to act as the transcriptional repressor in this process. However, the complete list of its gene targets is not known.</p> <p>Results</p> <p>Here, we deciphered the CRE1 regulatory range in the model cellulose and hemicellulose-degrading fungus <it>Trichoderma reesei </it>(anamorph of <it>Hypocrea jecorina</it>) by profiling transcription in a wild-type and a delta-<it>cre1 </it>mutant strain on glucose at constant growth rates known to repress and de-repress CCR-affected genes. Analysis of genome-wide microarrays reveals 2.8% of transcripts whose expression was regulated in at least one of the four experimental conditions: 47.3% of which were repressed by CRE1, whereas 29.0% were actually induced by CRE1, and 17.2% only affected by the growth rate but CRE1 independent. Among CRE1 repressed transcripts, genes encoding unknown proteins and transport proteins were overrepresented. In addition, we found CRE1-repression of nitrogenous substances uptake, components of chromatin remodeling and the transcriptional mediator complex, as well as developmental processes.</p> <p>Conclusions</p> <p>Our study provides the first global insight into the molecular physiological response of a multicellular fungus to carbon catabolite regulation and identifies several not yet known targets in a growth-controlled environment.</p

The weakest link: competence and prestige as constraints to referral by isolated nurses in rural Niger

BACKGROUND: For a health district to function referral from health centres to district hospitals is critical. In many developing countries referral systems perform well below expectations. Niger is not an exception in this matter. Beyond obvious problems of cost and access this study shows to what extent the behaviour of the health worker in its interaction with the patient can be a barrier of its own. METHODS: Information was triangulated from three sources in two rural districts in Niger: first, 46 semi-structured interviews with health centre nurses; second, 42 focus group discussions with an average of 12 participants – patients, relatives of patients and others; third, 231 semi-structured interviews with referred patients. RESULTS: Passive patients without 'voice' reinforce authoritarian attitudes of health centre staff. The latter appear reluctant to refer because they see little added value in referral and fear loss of power and prestige. As a result staff communicates poorly and show little eagerness to convince reluctant patients and families to accept referral proposals. CONCLUSIONS: Diminishing referral costs and distance barriers is not enough to correct failing referral systems. There is also a need for investment in district hospitals to make referrals visibly worthwhile and for professional upgrading of the human resources at the first contact level, so as to allow for more effective referral patterns

Identification and Comparative Expression Analysis of Interleukin 2/15 Receptor β Chain in Chickens Infected with E. tenella

BACKGROUND: Interleukin (IL) 2 and IL15 receptor β chain (IL2/15Rβ, CD122) play critical roles in signal transduction for the biological activities of IL2 and IL15. Increased knowledge of non-mammalian IL2/15Rβ will enhance the understanding of IL2 and IL15 functions. METHODOLOGY/PRINCIPAL FINDINGS: [corrected] Chicken IL2/15Rβ (chIL2/15Rβ) cDNA was cloned using 5'/3'-RACE. The predicted protein sequence contained 576 amino acids and typical features of the type-I cytokine receptor family. COS-7 cells transfected with chIL2/15Rβ produced proteins of approximately 75 and 62.5 kDa under normal and tunicamycin-treated conditions, respectively. The genomic structure of chIL2/15Rβ was similar to its mammalian counterparts. chIL2/15Rβ transcripts were detected in the lymphoblast cell line CU205 and in normal lymphoid organs and at moderate levels in bursa samples. Expression profiles of chIL2/15Rβ and its related cytokines and receptors were examined in ConA-stimulated splenic lymphocytes and in ceca-tonsils of Eimeria tenella-infected chickens using quantitative real-time PCR. Expression levels of chIL2/15Rβ, chIL2Rα, and chIL15Rα were generally elevated in ceca-tonsils and ConA-activated splenic lymphocytes. However, chIL2 and chIL15 expression levels were differentially regulated between the samples. chIL2 expression was upregulated in ConA-activated splenic lymphocytes, but not in ceca-tonsils. In constrast, chIL15 expression was upregulated in ceca-tonsils, but not in ConA-activated splenic lymphocytes. CONCLUSIONS/SIGNIFICANCE: We identified an avian form of IL2/15Rβ and compared its gene expression pattern with those of chIL2, chIL15, chIL2Rα, and chIL15Rα. Our observations suggest that chIL15 and its receptors, including chIL2/15Rβ, play important roles in mucosal immunity to intestinal intracellular parasites such as Eimeria

OH reactivity in urban and suburban regions in Seoul, South Korea – an East Asian megacity in a rapid transition

South Korea has recently achieved developed country status with the second largest megacity in the world, the Seoul Metropolitan Area (SMA). This study provides insights into future changes in air quality for rapidly emerging megacities in the East Asian region. We present total OH reactivity observations in the SMA conducted at an urban Seoul site (May-June, 2015) and a suburban forest site (Sep, 2015). The total OH reactivity in an urban site during the daytime was observed at similar levels (∼15 s(-1)) to those previously reported from other East Asian megacity studies. Trace gas observations indicate that OH reactivity is largely accounted for by NOX (∼50%) followed by volatile organic compounds (VOCs) (∼35%). Isoprene accounts for a substantial fraction of OH reactivity among the comprehensive VOC observational dataset (25-47%). In general, observed total OH reactivity can be accounted for by the observed trace gas dataset. However, observed total OH reactivity in the suburban forest area cannot be largely accounted for (∼70%) by the trace gas measurements. The importance of biogenic VOC (BVOCs) emissions and oxidations used to evaluate the impacts of East Asian megacity outflows for the regional air quality and climate contexts are highlighted in this study