IL-10 production in macrophages is regulated by a TLR-driven CREB-mediated mechanism that is linked to genes involved in cell metabolism

IL-10 is produced by macrophages in diverse immune settings and is critical in limiting immune-mediated pathology. In helminth infections, macrophages are an important source of IL-10; however, the molecular mechanism underpinning production of IL-10 by these cells is poorly characterized. In this study, bone marrow–derived macrophages exposed to excretory/secretory products released by Schistosoma mansoni cercariae rapidly produce IL-10 as a result of MyD88-mediated activation of MEK/ERK/RSK and p38. The phosphorylation of these kinases was triggered by TLR2 and TLR4 and converged on activation of the transcription factor CREB. Following phosphorylation, CREB is recruited to a novel regulatory element in the Il10 promoter and is also responsible for regulating a network of genes involved in metabolic processes, such as glycolysis, the tricarboxylic acid cycle, and oxidative phosphorylation. Moreover, skin-resident tissue macrophages, which encounter S. mansoni excretory/secretory products during infection, are the first monocytes to produce IL-10 in vivo early postinfection with S. mansoni cercariae. The early and rapid release of IL-10 by these cells has the potential to condition the dermal microenvironment encountered by immune cells recruited to this infection site, and we propose a mechanism by which CREB regulates the production of IL-10 by macrophages in the skin, but also has a major effect on their metabolic state

CD4+ T cell hyporesponsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10

The effect that multiple percutaneous exposures to Schistosoma larvae has on the development of early CD4+ lymphocyte reactivity is unclear, yet it is important in the context of humans living in areas where schistosomiasis is endemic. In a murine model of multiple infections, we show that exposure of mice to repeated doses (4×) of Schistosoma mansoni cercariae, compared to a single dose (1×), results in CD4+ T cell hyporesponsiveness within the skin-draining lymph nodes (sdLN), manifested as reduced CD4+ cell proliferation and cytokine production. FoxP3+ CD4+ regulatory T cells were present in similar numbers in the sdLN of 4× and 1× mice and thus are unlikely to have a role in effecting hyporesponsiveness. Moreover, anergy of the CD4+ cell population from 4× mice was slight, as proliferation was only partly circumvented through the in vitro addition of exogenous interleukin-2 (IL-2), and the in vivo blockade of the regulatory molecule PD1 had a minimal effect on restoring responsiveness. In contrast, IL-10 was observed to be critical in mediating hyporesponsiveness, as CD4+ cells from the sdLN of 4× mice deficient for IL-10 were readily able to proliferate, unlike those from 4× wild-type cohorts. CD4+ cells from the sdLN of 4× mice exhibited higher levels of apoptosis and cell death, but in the absence of IL-10, there was significantly less cell death. Combined, our data show that IL-10 is a key factor in the development of CD4+ T cell hyporesponsiveness after repeated parasite exposure involving CD4+ cell apoptosis

Nurses\u27 Alumnae Association Bulletin - Volume 5 Number 8

Calling All Nurses Financial Report Calendar of Events Lest You Forget! Attention Review of the Alumnae Association Meetings President\u27s Report Barton Memorial Division Oxygen Therapy Welcome, White Haven Alumnae Clinical Use of Penicillin in Infections of the Ears, Nose and Throat Address - Graduation of Nurses, 1945 Miscellaneous Items The Blood that Kills The Story of Malaria Program Prizes - May, 1946 Capping Exercises The Economic Security Program of the Pennsylvania State Nurses\u27 Association The Clara Melville Scholarship Fund Card of Thanks The Poet\u27s Corner The Hospital Pharmacy Jefferson Medical College Hospital School of Nursing Faculty Jefferson Hospital Gray Lady Unite, A.R.R. The Volunteer Nurses\u27 Aides Salute Jefferson Nurses Changes in the Staff at Jefferson Hospital Red Cross Recruits Did You Know That The Pennsylvania Nurse Medical College News Magazine and Newspaper Items Central Dressing Room and Transfusion Unit Rules Concerning Central Dressing Room Radios and Electrical Appliances Attending College Nurses in Anesthesia Condolences Marriages New Arrivals Deaths The Bulletin Committee Attention, Alumnae New Addresse

Unexpected benefits of pre-university skills training for A-level students

First-year undergraduates can find the transition from the prescriptive learning environment at school to one of self-directed learning at university, a considerable challenge. A Pre-university Skills Course (PSC) was developed to address this issue by preparing sixth formers for the university learning style. It was piloted with students in the year prior to A-level examinations at a selective state-funded school in East Anglia. The present paper examines the effect of the course on the students’ A-level tariff. Chi-squared analysis of A-level grades of students with comparable GCSE results, indicate that students who undertook the PSC performed significantly better in their A-level results than those who did not. These data demonstrate how skills training might improve A-level performance and assist in the transition to university

Optimization of inhomogeneous electron correlation factors in periodic solids

A method is presented for the optimization of one-body and inhomogeneous two-body terms in correlated electronic wave functions of Jastrow-Slater type. The most general form of inhomogeneous correlation term which is compatible with crystal symmetry is used and the energy is minimized with respect to all parameters using a rapidly convergent iterative approach, based on Monte Carlo sampling of the energy and fitting energy fluctuations. The energy minimization is performed exactly within statistical sampling error for the energy derivatives and the resulting one- and two-body terms of the wave function are found to be well-determined. The largest calculations performed require the optimization of over 3000 parameters. The inhomogeneous two-electron correlation terms are calculated for diamond and rhombohedral graphite. The optimal terms in diamond are found to be approximately homogeneous and isotropic over all ranges of electron separation, but exhibit some inhomogeneity at short- and intermediate-range, whereas those in graphite are found to be homogeneous at short-range, but inhomogeneous and anisotropic at intermediate- and long-range electron separation.Comment: 23 pages, 15 figures, 1 table, REVTeX4, submitted to PR

Self-healing in B12P2 through Mediated Defect Recombination

Citation: Self-healing in B12P2 through Mediated Defect Recombination. S. P. Huber, E. Gullikson, C. D. Frye, J. H. Edgar, R. W. E. van de Kruijs, F. Bijkerk, and D. Prendergast. Chemistry of Materials 28 8415--8428 (2016) 10.1021/acs.chemmater.6b04075The icosahedral boride B12P2 has been reported to exhibit “self-healing” properties, after transmission electron microscopy recordings of sample surfaces, which were exposed to highly energetic particle beams, revealed little to no damage. In this work, employing calculations from first-principles within the density functional theory (DFT) framework, the structural characteristics of boron interstitial and vacancy defects in B12P2 are investigated. Using nudged elastic band simulations, the diffusion properties of interstitial and vacancy defects and their combination, in the form of Frenkel defect pairs, are studied. We find that boron icosahedra maintain their structural integrity even when in a degraded state in the presence of a vacancy or interstitial defect and that the diffusion activation energy for the recombination of an interstitial vacany pair can be as low as 3 meV, in line with the previously reported observation of “self-healing”

Precession of a Freely Rotating Rigid Body. Inelastic Relaxation in the Vicinity of Poles

When a solid body is freely rotating at an angular velocity ${\bf \Omega}$, the ellipsoid of constant angular momentum, in the space $\Omega_1, \Omega_2, \Omega_3$, has poles corresponding to spinning about the minimal-inertia and maximal-inertia axes. The first pole may be considered stable if we neglect the inner dissipation, but becomes unstable if the dissipation is taken into account. This happens because the bodies dissipate energy when they rotate about any axis different from principal. In the case of an oblate symmetrical body, the angular velocity describes a circular cone about the vector of (conserved) angular momentum. In the course of relaxation, the angle of this cone decreases, so that both the angular velocity and the maximal-inertia axis of the body align along the angular momentum. The generic case of an asymmetric body is far more involved. Even the symmetrical prolate body exhibits a sophisticated behaviour, because an infinitesimally small deviation of the body's shape from a rotational symmetry (i.e., a small difference between the largest and second largest moments of inertia) yields libration: the precession trajectory is not a circle but an ellipse. In this article we show that often the most effective internal dissipation takes place at twice the frequency of the body's precession. Applications to precessing asteroids, cosmic-dust alignment, and rotating satellites are discussed.Comment: 47 pages, 1 figur

Monitoring and Pay: An Experiment on Employee Performance under Endogenous Supervision

We present an experimental test of a shirking model where monitoring intensity is endogenous and effort a continuous variable. Wage level, monitoring intensity and consequently the desired enforceable effort level are jointly determined by the maximization problem of the firm. As a result, monitoring and pay should be complements. In our experiment, between and within treatment variation is qualitatively in line with the normative predictions of the model under standard assumptions. Yet, we also find evidence for reciprocal behavior. Our data analysis shows, however, that it does not pay for the employer to solely rely on the reciprocity of employees