De-novo design of complementary (antisense) peptide mini-receptor inhibitor of interleukin 18 (IL-18).

Complementary (antisense) peptide mini-receptor inhibitors are complementary peptides designed to be receptor-surrogates that act by binding to selected surface features of biologically important proteins thereby inhibiting protein-cognate receptor interactions and subsequent biological effects. Previously, we described a complementary peptide mini-receptor inhibitor of interleukin-1beta (IL-1beta) that was designed to bind to an external surface loop (beta-bulge) of IL-1beta (Boraschi loop) clearly identified in the X-ray crystal structure of this cytokine. Here, we report the de-novo design and rational development of a complementary peptide mini-receptor inhibitor of cytokine interleukin-18 (IL-18), a protein for which there is no known X-ray crystal structure. Using sequence homology comparisons with IL-1beta, putative IL-18 surface loops are identified and used as a starting point for design, including a loop region 1 thought to be equivalent with the Boraschi loop of IL-1beta. Only loop region 1 complementary peptides are found to be promising leads as mini-receptor inhibitors of IL-18 but these are prevented from being properly successful owing to solubility problems. The application of "M-I pair mutagenesis" and inclusion of a C-terminal arginine residue are then sufficient to solve this problem and convert one lead peptide into a functional complementary peptide mini-receptor inhibitor of IL-18. This suggests that the biophysical and biological properties of complementary peptides can be improved in a rational and logical manner where appropriate, further strengthening the potential importance of complementary peptides as inhibitors of protein-protein interactions, even when X-ray crystal structural information is not readily available

Antiviral cellular therapy for enhancing T-cell reconstitution before or after hematopoietic stem cell transplantation (ACES): A two-arm, open label phase II interventional trial of pediatric patients with risk factor assessment

Viral infections remain a major risk in immunocompromised pediatric patients, and virus-specific T cell (VST) therapy has been successful for treatment of refractory viral infections in prior studies. We performed a phase II multicenter study (NCT03475212) for the treatment of pediatric patients with inborn errors of immunity and/or post allogeneic hematopoietic stem cell transplant with refractory viral infections using partially-HLA matched VSTs targeting cytomegalovirus, Epstein-Barr virus, or adenovirus. Primary endpoints were feasibility, safety, and clinical responses (\u3e1 log reduction in viremia at 28 days). Secondary endpoints were reconstitution of antiviral immunity and persistence of the infused VSTs. Suitable VST products were identified for 75 of 77 clinical queries. Clinical responses were achieved in 29 of 47 (62%) of patients post-HSCT including 73% of patients evaluable at 1-month post-infusion, meeting the primary efficacy endpoint (\u3e52%). Secondary graft rejection occurred in one child following VST infusion as described in a companion article. Corticosteroids, graft-versus-host disease, transplant-associated thrombotic microangiopathy, and eculizumab treatment correlated with poor response, while uptrending absolute lymphocyte and CD8 T cell counts correlated with good response. This study highlights key clinical factors that impact response to VSTs and demonstrates the feasibility and efficacy of this therapy in pediatric HSCT

Soil–Atmosphere Exchange of Nitrous Oxide, Nitric Oxide, Methane, and Carbon Dioxide in Logged and Undisturbed Forest in the Tapajos National Forest, Brazil

Selective logging is an extensive land use in the Brazilian Amazon region. The soil–atmosphere fluxes of nitrous oxide (N2O), nitric oxide (NO), methane (CH4), and carbon dioxide (CO2) are studied on two soil types (clay Oxisol and sandy loam Ultisol) over two years (2000–01) in both undisturbed forest and forest recently logged using reduced impact forest management in the Tapajos National Forest, near Santarem, Para, Brazil. In undisturbed forest, annual soil–atmosphere fluxes of N2O (mean ± standard error) were 7.9 ± 0.7 and 7.0 ± 0.6 ng N cm−2 h−1 for the Oxisol and 1.7 ± 0.1 and 1.6 ± 0.3 ng N cm−2 h−1 for the Ultisol for 2000 and 2001, respectively. The annual fluxes of NO from undisturbed forest soil in 2001 were 9.0 ± 2.8 ng N cm−2 h−1 for the Oxisol and 8.8 ± 5.0 ng N cm−2 h−1 for the Ultisol. Consumption of CH4 from the atmosphere dominated over production on undisturbed forest soils. Fluxes averaged −0.3 ± 0.2 and −0.1 ± 0.9 mg CH4 m−2 day−1 on the Oxisol and −1.0 ± 0.2 and −0.9 ± 0.3 mg CH4 m−2 day−1 on the Ultisol for years 2000 and 2001. For CO2 in 2001, the annual fluxes averaged 3.6 ± 0.4 μmol m−2 s−1 on the Oxisol and 4.9 ± 1.1 μmol m−2 s−1 on the Ultisol. We measured fluxes over one year each from two recently logged forests on the Oxisol in 2000 and on the Ultisol in 2001. Sampling in logged areas was stratified from greatest to least ground disturbance covering log decks, skid trails, tree-fall gaps, and forest matrix. Areas of strong soil compaction, especially the skid trails and logging decks, were prone to significantly greater emissions of N2O, NO, and especially CH4. In the case of CH4, estimated annual emissions from decks reached extremely high rates of 531 ± 419 and 98 ± 41 mg CH4 m−2 day−1, for Oxisol and Ultisol sites, respectively, comparable to wetland emissions in the region. We calculated excess fluxes from logged areas by subtraction of a background forest matrix or undisturbed forest flux and adjusted these fluxes for the proportional area of ground disturbance. Our calculations suggest that selective logging increases emissions of N2O and NO from 30% to 350% depending upon conditions. While undisturbed forest was a CH4 sink, logged forest tended to emit methane at moderate rates. Soil–atmosphere CO2 fluxes were only slightly affected by logging. The regional effects of logging cannot be simply extrapolated based upon one site. We studied sites where reduced impact harvest management was used while in typical conventional logging ground damage is twice as great. Even so, our results indicate that for N2O, NO, and CH4, logging disturbance may be as important for regional budgets of these gases as other extensive land-use changes in the Amazon such as the conversion of forest to cattle pasture

Experimentally induced root mortality increased nitrous oxide emission from tropical forest soils

We conducted an experiment on sand and clay tropical forest soils to test the short‐term effect of root mortality on the soil‐atmosphere flux of nitrous oxide, nitric oxide, methane, and carbon dioxide. We induced root mortality by isolating blocks of land to 1 m using trenching and root exclusion screening. Gas fluxes were measured weekly for ten weeks following the trenching treatment. For nitrous oxide there was a highly significant increase in soil‐atmosphere flux over the ten weeks following treatment for trenched plots compared to control plots. N2O flux averaged 37.5 and 18.5 ng N cm−2 h−1 from clay trenched and control plots and 4.7 and 1.5 ng N cm−2 h−1 from sand trenched and control plots. In contrast, there was no effect for soil‐atmosphere flux of nitric oxide, carbon dioxide, or methane

Preparatory cortical and spinal settings to counteract anticipated and non-anticipated perturbations

Little is known about how the central nervous system prepares postural responses differently in anticipated compared to non-anticipated perturbations. To investigate this, participants were exposed to translational and rotational perturbations presented in a blocked (anticipated) and a random (non-anticipated) design. The preparatory setting (‘central set’) was measured by H-reflexes, motor-evoked potentials (MEPs), and short-interval intracortical inhibition (SICI) shortly before perturbation onset in the soleus of 15 healthy adults. Additionally, the behavioral consequences of differential preparatory settings were analyzed by comparing the short- (SLR), medium- (MLR), and long-latency response (LLR) of the soleus after anticipated and non-anticipated rotations and translations. H-reflexes elicited before perturbation were different between conditions (p=0.023) with larger amplitudes in anticipated translations compared to anticipated rotations (37.0%; p=0.048). Reduced SICI was found in the three conditions containing perturbations compared to static standing (p0.001). Muscular responses assessed after perturbations remained unchanged for the SLR and MLR, whereas the LLR was decreased in anticipated rotations (−36.2%; p=0.002) and increased in anticipated translations (16.7%; p=0.046) compared to the corresponding non-anticipated perturbation. As the SLR and MLR are organized at the spinal and the LLR at the cortical level, the preparatory setting seems to mainly influence cortically mediated postural responses. However, the modulation of the H- reflex before anticipated perturbations indicates that supraspinal centers adjusted Ia- afferent transmission for the soleus in a perturbation-specific manner. Intracortical inhibition was also modulated but differentiates to a lesser extent only between perturbation conditions and unperturbed stance

Fine root dynamics and trace gas fluxes in two lowland tropical forest soils

Fine root dynamics have the potential to contribute significantly to ecosystem-scale biogeochemical cycling, including the production and emission of greenhouse gases. This is particularly true in tropical forests which are often characterized as having large fine root biomass and rapid rates of root production and decomposition. We examined patterns in fine root dynamics on two soil types in a lowland moist Amazonian forest, and determined the effect of root decay on rates of C and N trace gas fluxes. Root production averaged 229 ( 35) and 153 ( 27) gm 2 yr 1 for years 1 and 2 of the study, respectively, and did not vary significantly with soil texture. Root decay was sensitive to soil texture with faster rates in the clay soil (k5 0.96 year 1) than in the sandy loam soil (k5 0.61 year 1),leading to greater standing stocks of dead roots in the sandy loam. Rates of nitrous oxide (N2O) emissions were significantly greater in the clay soil (13 1ngNcm 2 h 1) than in the sandy loam (1.4 0.2 ngNcm 2 h 1). Root mortality and decay following trenching doubled rates of N2O emissions in the clay and tripled them in sandy loam over a 1-year period. Trenching also increased nitric oxide fluxes, which were greater in the sandy loam than in the clay. We used trenching (clay only) and a mass balance approach to estimate the root contribution to soil respiration. In clay soil root respiration was 264–380 gCm 2 yr 1, accounting for 24% to 35% of the total soil CO2 efflux. Estimates were similar using both approaches. In sandy loam, root respiration rates were slightly higher and more variable (521 206 gCm2 yr 1) and contributed 35% of the total soil respiration. Our results show that soil heterotrophs strongly dominate soil respiration in this forest, regardless of soil texture. Our results also suggest that fine root mortality and decomposition associated with disturbance and land-use change can contribute significantly to increased rates of nitrogen trace gas emissions

Hubble Space Telescope Observations of Comet 9P/Tempel 1 during the Deep Impact Encounter

We report on the Hubble Space Telescope program to observe periodic comet 9P/Tempel 1 in conjunction with NASA's Deep Impact mission. Our objectives were to study the generation and evolution of the coma resulting from the impact and to obtain wide-band images of the visual outburst generated by the impact. Two observing campaigns utilizing a total of 17 HST orbits were carried out: the first occurred on 2005 June 13-14 and fortuitously recorded the appearance of a new, short-lived fan in the sunward direction on June 14. The principal campaign began two days before impact and was followed by contiguous orbits through impact plus several hours and then snapshots one, seven, and twelve days later. All of the observations were made using the Advanced Camera for Surveys (ACS). For imaging, the ACS High Resolution Channel (HRC) provides a spatial resolution of 36 km (16 km/pixel) at the comet at the time of impact. Baseline images of the comet, made prior to impact, photometrically resolved the comet's nucleus. The derived diameter, 6.1 km, is in excellent agreement with the 6.0 +/- 0.2 km diameter derived from the spacecraft imagers. Following the impact, the HRC images illustrate the temporal and spatial evolution of the ejecta cloud and allow for a determination of its expansion velocity distribution. One day after impact the ejecta cloud had passed out of the field-of-view of the HRC.Comment: 15 pages, 14 postscript figures. Accepted for publication in Icarus special issue on Deep Impac

Continuous Equilibrium in Affine and Information-Based Capital Asset Pricing Models

We consider a class of generalized capital asset pricing models in continuous time with a finite number of agents and tradable securities. The securities may not be sufficient to span all sources of uncertainty. If the agents have exponential utility functions and the individual endowments are spanned by the securities, an equilibrium exists and the agents' optimal trading strategies are constant. Affine processes, and the theory of information-based asset pricing are used to model the endogenous asset price dynamics and the terminal payoff. The derived semi-explicit pricing formulae are applied to numerically analyze the impact of the agents' risk aversion on the implied volatility of simultaneously-traded European-style options.Comment: 24 pages, 4 figure

Postpartum urinary retention: what are the sequelae? A long-term study and review of the literature.

INTRODUCTION AND HYPOTHESIS Postpartum urinary retention (PUR) may cause long-term urogenital tract morbidity. The incidence ranges from 0.18 to 14.6%, but the importance of prompt diagnosis and appropriate management is often underappreciated. The paucity of data on long-term outcome after PUR contributes to these drawbacks. The aim of this study was to assess long-term persistence of elevated PVR (post-void residual urine) volume after PUR. Pathophysiology, risk factors and management of PUR are reviewed. METHODS In our tertiary referral urogynecology unit in the University Women's Hospital of Bern, Switzerland, all patients who were referred for PUR were asked to participate in this study. PVR was measured sonographically every 2 days until day 15, then after 6, 12, 24 and 36 months and, if increased, the patients were instructed to perform clean intermittent self-catheterization. If retention persisted longer than the lactation period, multichannel urodynamics was performed. RESULTS Sixty-two patients were included. The median PVR normalized at day 7. Long-term voiding disorders were found in 8.2%, 6.7%, and 4.9% after 1, 2, and 3 years respectively. Multichannel urodynamics confirmed in all patients with persisting retention an acontractile detrusor and de novo stress urinary incontinence in 4 cases. Quantile regression did not reveal any factor contributing to earlier recovery. Eighty-nine percent of the patients with PUR had operative vaginal deliveries, emphasizing the importance of this risk factor for PUR. CONCLUSIONS In most cases PUR resolves early, but voiding difficulties persist more often than previously thought, and for these patients the consequences are devastating. Obstetric awareness, early active management, and developing management strategies in the postpartum period might preclude lower urinary tract morbidity