IL-12 and IL-4 activate a CD39-dependent intrinsic peripheral tolerance mechanism in CD8+ T cells

Immune responses to protein antigens involve CD4+ and CD8+ T cells, which follow distinct programs of differentiation. Naïve CD8 T cells rapidly develop cytotoxic T-cell (CTL) activity after T-cell receptor stimulation, and we have previously shown that this is accompanied by suppressive activity in the presence of specific cytokines, i.e. IL-12 and IL-4. Cytokine-induced CD8+ regulatory T (Treg) cells are one of several Treg-cell phenotypes and are Foxp3− IL-10+ with contact-dependent suppressive capacity. Here, we show they also express high level CD39, an ecto-nucleotidase that degrades extracellular ATP, and this contributes to their suppressive activity. CD39 expression was found to be upregulated on CD8+ T cells during peripheral tolerance induction in vivo, accompanied by release of IL-12 and IL-10. CD39 was also upregulated during respiratory tolerance induction to inhaled allergen and on tumor-infiltrating CD8+ T cells. Production of IL-10 and expression of CD39 by CD8+ T cells was independently regulated, being respectively blocked by extracellular ATP and enhanced by an A2A adenosine receptor agonist. Our results suggest that any CTL can develop suppressive activity when exposed to specific cytokines in the absence of alarmins. Thus negative feedback controls CTL expansion under regulation from both nucleotide and cytokine environment within tissues

Reliability of perceptions of voice quality: evidence from a problem asthma clinic population

<p>Introduction: Methods of perceptual voice evaluation have yet to achieve satisfactory consistency; complete acceptance of a recognised clinical protocol is still some way off.</p> <p>Materials and methods: Three speech and language therapists rated the voices of 43 patients attending the problem asthma clinic of a teaching hospital, according to the grade-roughness-breathiness-asthenicity-strain (GRBAS) scale and other perceptual categories.</p> <p>Results and analysis: Use of the GRBAS scale achieved only a 64.7 per cent inter-rater reliability and a 69.6 per cent intra-rater reliability for the grade component. One rater achieved a higher degree of consistency. Improved concordance on the GRBAS scale was observed for subjects with laryngeal abnormalities. Raters failed to reach any useful level of agreement in the other categories employed, except for perceived gender.</p> <p>Discussion: These results should sound a note of caution regarding routine adoption of the GRBAS scale for characterising voice quality for clinical purposes. The importance of training and the use of perceptual anchors for reliable perceptual rating need to be further investigated.</p&gt

Changes in Older and Younger Woods in West-Central Ohio

Author Institution: Dept. of Biological Sciences, Wright State University, OHThis study examines changes in two forest stands in the Quercus-Acer saccharum forest region of west central Ohio: an old-growth stand changing from Quercus-dominated to Acer saccharum-dominated and a stand established following agricultural abandonment about 1950. Both stands are in the Wright State University woods. Permanent plots were sampled in 1980 (younger stand only), 1982 (older stand only), 1993, and 2000. The older stand had more small, fewer intermediate, and more large stems than the younger stand. The plot in the new stand showed a bell-shaped distribution with most stems established shortly after land abandonment. Mortality decreased and growth increased with stem size for both stands. Acer saccharum in all sizes and large Quercus dominated the older stand. The younger stand was dominated by Robinia pseudo-acacia with Acer saccharum also important. In the older plots small stems generally were clustered, intermediate-sized stems randomly distributed, and the largest stems regularly distributed. In the younger plot small stems were aggregated while larger ones were randomly distributed. Quercus regenerated well until the late 1800s, singly or in small groups, but few stems have become established since 1900. Quercus may need fires or grazing to regenerate successfully. Both stands are changing to increased dominance by Acer saccharum and other shade-tolerant species as they lose species (Robinia pseudo-acacia in the younger stand, Quercus in the older stand) more successful under past than present conditions

Probing the Sensitivity of Electron Wave Interference to Disorder-Induced Scattering in Solid-State Devices

The study of electron motion in semiconductor billiards has elucidated our understanding of quantum interference and quantum chaos. The central assumption is that ionized donors generate only minor perturbations to the electron trajectories, which are determined by scattering from billiard walls. We use magnetoconductance fluctuations as a probe of the quantum interference and show that these fluctuations change radically when the scattering landscape is modified by thermally-induced charge displacement between donor sites. Our results challenge the accepted understanding of quantum interference effects in nanostructures.Comment: 8 pages, 5 figures, Submitted to Physical Review

Multimodal perioperative pain protocol for gynecologic oncology laparotomy is associated with reduced hospital length of stay and improved patient pain scores

The primary objective was to evaluate the impact of a multimodal perioperative pain regimen on length of hospital stay for patients undergoing laparotomy with a gynecologic oncologist

Metabolite and thymocyte development defects in ADA-SCID mice receiving enzyme replacement therapy

Deficiency of adenosine deaminase (ADA, EC3.5.4.4), a housekeeping enzyme intrinsic to the purine salvage pathway, leads to severe combined immunodeficiency (SCID) both in humans and mice. Lack of ADA results in the intracellular accumulation of toxic metabolites which have effects on T cell development and function. While untreated ADA-SCID is a fatal disorder, there are different therapeutic options available to restore ADA activity and reconstitute a functioning immune system, including enzyme replacement therapy (ERT). Administration of ERT in the form of pegylated bovine ADA (PEG-ADA) has proved a life-saving though non-curative treatment for ADA-SCID patients. However, in many patients treated with PEG-ADA, there is suboptimal immune recovery with low T and B cell numbers. Here, we show reduced thymus cellularity in ADA-SCID mice despite weekly PEG-ADA treatment. This was associated with lack of effective adenosine (Ado) detoxification in the thymus. We also show that thymocyte development in ADA-deficient thymi is arrested at the DN3-to-DN4 stage transition with thymocytes undergoing dATP-induced apoptosis rather than defective TCRβ rearrangement or β-selection. Our studies demonstrate at a detailed level that exogenous once-a-week enzyme replacement does not fully correct intra-thymic metabolic or immunological abnormalities associated with ADA deficiency

Ecological and Genomic Attributes of Novel Bacterial Taxa That Thrive in Subsurface Soil Horizons.

While most bacterial and archaeal taxa living in surface soils remain undescribed, this problem is exacerbated in deeper soils, owing to the unique oligotrophic conditions found in the subsurface. Additionally, previous studies of soil microbiomes have focused almost exclusively on surface soils, even though the microbes living in deeper soils also play critical roles in a wide range of biogeochemical processes. We examined soils collected from 20 distinct profiles across the United States to characterize the bacterial and archaeal communities that live in subsurface soils and to determine whether there are consistent changes in soil microbial communities with depth across a wide range of soil and environmental conditions. We found that bacterial and archaeal diversity generally decreased with depth, as did the degree of similarity of microbial communities to those found in surface horizons. We observed five phyla that consistently increased in relative abundance with depth across our soil profiles: Chloroflexi, Nitrospirae, Euryarchaeota, and candidate phyla GAL15 and Dormibacteraeota (formerly AD3). Leveraging the unusually high abundance of Dormibacteraeota at depth, we assembled genomes representative of this candidate phylum and identified traits that are likely to be beneficial in low-nutrient environments, including the synthesis and storage of carbohydrates, the potential to use carbon monoxide (CO) as a supplemental energy source, and the ability to form spores. Together these attributes likely allow members of the candidate phylum Dormibacteraeota to flourish in deeper soils and provide insight into the survival and growth strategies employed by the microbes that thrive in oligotrophic soil environments.IMPORTANCE Soil profiles are rarely homogeneous. Resource availability and microbial abundances typically decrease with soil depth, but microbes found in deeper horizons are still important components of terrestrial ecosystems. By studying 20 soil profiles across the United States, we documented consistent changes in soil bacterial and archaeal communities with depth. Deeper soils harbored communities distinct from those of the more commonly studied surface horizons. Most notably, we found that the candidate phylum Dormibacteraeota (formerly AD3) was often dominant in subsurface soils, and we used genomes from uncultivated members of this group to identify why these taxa are able to thrive in such resource-limited environments. Simply digging deeper into soil can reveal a surprising number of novel microbes with unique adaptations to oligotrophic subsurface conditions

Empirical Determination of Bang-Bang Operations

Strong and fast "bang-bang" (BB) pulses have been recently proposed as a means for reducing decoherence in a quantum system. So far theoretical analysis of the BB technique relied on model Hamiltonians. Here we introduce a method for empirically determining the set of required BB pulses, that relies on quantum process tomography. In this manner an experimenter may tailor his or her BB pulses to the quantum system at hand, without having to assume a model Hamiltonian.Comment: 14 pages, 2 eps figures, ReVTeX4 two-colum

Multimodal perioperative pain protocol for Gynecologic Oncology laparotomy reduces length of hospital stay

Our primary objective was to evaluate the impact of a multimodal perioperative pain regimen on length of hospital stay for patients undergoing laparotomy with a gynecologic oncologist

Conversion to sirolimus for chronic renal allograft dysfunction: risk factors for graft loss and severe side effects

We retrospectively reviewed our experience with 45 kidney transplant recipients (KTR) that were switched from CNI to SRL, mainly for chronic allograft dysfunction (CAD) (41/45). The mean serum creatinine at switch was 2.5 ± 0.8 mg/dl. At 1 year, patient survival was 93%. Death-censored graft survival was 67% at 1 year and 54% at 2 years. SRL was stopped because of severe side effects in 15 patients. Among these, eight patients developed ‘de novo’ high-grade proteinuria. Univariate analysis revealed that (1) a higher SRL level at 1 month was a predictor of SRL withdrawal due to severe side effects (P = 0.006), and (2) predictors of graft failure after SRL conversion were low SRL loading dose (P = 0.03) and a higher creatinine level at conversion (P = 0.003)