Targeted pharmacologic activation of antigen-specific (AgS) T cells may bypass limitations inherent in current T cell-based cancer therapies. We describe two immunotherapeutics platforms for ...selective delivery of costimulatory ligands and peptide-HLA (pHLA) to AgS T cells. We engineered and deployed on these platforms an affinity-attenuated variant of interleukin-2, which selectively expands oligoclonal and polyfunctional AgS T cells in vitro and synergizes with CD80 signals for superior proliferation versus peptide stimulation.
Metabolic pathways in eubacteria and archaea often are encoded by operons and/or gene clusters (genome neighborhoods) that provide important clues for assignment of both enzyme functions and ...metabolic pathways. We describe a bioinformatic approach (genome neighborhood network; GNN) that enables large scale prediction of the in vitro enzymatic activities and in vivo physiological functions (metabolic pathways) of uncharacterized enzymes in protein families. We demonstrate the utility of the GNN approach by predicting in vitro activities and in vivo functions in the proline racemase superfamily (PRS; InterPro IPR008794). The predictions were verified by measuring in vitro activities for 51 proteins in 12 families in the PRS that represent ∼85% of the sequences; in vitro activities of pathway enzymes, carbon/nitrogen source phenotypes, and/or transcriptomic studies confirmed the predicted pathways. The synergistic use of sequence similarity networks3 and GNNs will facilitate the discovery of the components of novel, uncharacterized metabolic pathways in sequenced genomes.
The study investigated the ability of near-infrared spectroscopy (NIRS) to detect subgroups of preterm infants who benefit most from red blood cell (RBC) transfusion in regard to cerebral/renal ...tissue oxygenation (i) and the number of general oxygen desaturation below 80% (SaO(2) <80%) (ii).
Cerebral regional (crSO(2)) and peripheral regional (prSO(2)) NIRS parameters were recorded before, during, immediately after and 24 h after transfusion in 76 infants. Simultaneously, SaO(2) <80% were recorded by pulse oximetry. To answer the basic question of the study, all preterm infants were divided into two subgroups according to their pretransfusion crSO(2) values (<55% and ≥55%). This cutoff was determined by a k-means clustering analysis.
crSO(2) and prSO(2) increased significantly in the whole study population. A stronger increase (P<0.0005) of both was found in the subgroup with pretransfusion crSO(2) values <55%. Regarding the whole population, a significant decrease (P<0.05) of episodes with SaO(2) <80% was observed. The subgroup with crSO(2) baselines <55% had significant (P<0.05) more episodes with SaO(2) <80% before transfusion. During and after transfusion, the frequency of episodes with SaO(2) <80% decreased more in this group compared with the group with crSO(2) baselines ≥55%.
NIRS measurement is a simple, non-invasive method to monitor regional tissue oxygenation and the efficacy of RBC transfusion. Infants with low initial NIRS values benefited most from blood transfusions regarding SaO(2) <80%, which may be important for their general outcome.
Light is one of the most critical factors controlling tree survival and growth. Limited light availability induces phenotypic plasticity, thus enabling plants to adapt to suboptimal conditions. The ...plastic responses are species-specific and are thought to largely depend on species’ shade tolerance. This study aims to add to existing research by trying to disentangle the effects of light, species identity, and shade tolerance on growth, biomass partitioning, and morphology of seedlings of seven common European tree species. For that purpose, we set up a shading experiment where seedlings were grown under three levels of light availability (15%, 35%, and 100%). A destructive harvest was carried out for the assessment of biomass allocation and structural complexity of plant architecture after a year of exposure to limited light. The specific leaf area increased with decreasing light availability for all species. However, we found little to no changes in relative height and diameter growth, biomass allocation to aboveground tree compartments, and structural complexity along the light gradient. We argue that because trees were grown under open field conditions, both in the nursery and for the first year of the experiment, it might have resulted in a delayed response to limited light availability. Assuming the delayed reaction of less plastic plant organs, we expect that the morphological adaptations of the tree species and intra- and interspecific differences will become more pronounced, as the trees grow older.
At 5 to 6 years of age, body fatness normally declines to a minimum, a point called adiposity rebound (AR), before increasing again into adulthood. We determined whether a younger age at AR was ...associated with an increased risk of adult obesity and whether this risk was independent of fatness at AR and parent obesity.
A retrospective cohort study using lifelong height and weight measurements recorded in outpatient medical records.
Group Health Cooperative of Puget Sound (GHC), a health maintenance organization based in Seattle, Washington.
All 390 GHC members (and their parents) born at GHC between January 1, 1965, and January 1, 1971, who had at least one recorded adult height and weight measurement plus two visits with recorded height and weight measurements in each of three age intervals: 1.5 to 4, 4 to 8, and 8 to 16 years.
We calculated the mean body mass index (BMI) of each subject during young adulthood (age 21 to 29 years) and the BMI of the parents when each subject was 1.5 years of age. Adult obesity was defined as a BMI >/=27.8 for males and >/=27. 3 for females. Curves were fit to each subject's BMI values between ages 1.5 and 16 years, and the age and BMI at AR were calculated from these curves. Subjects were divided into tertiles of age at AR (early, middle, and late), BMI at AR, and parent BMI (heavy, medium, and lean).
The mean age at AR was 5.5 years, and 15% of the cohort was obese in young adulthood. Adult obesity rates were higher in those with early versus late AR (25% vs 5%), those who were heavy versus lean at AR (24% vs 4%), those with heavy versus lean mothers (25% vs 5%), and those with heavy versus lean fathers (21% vs 5%). After adjusting for parent BMI and BMI at AR, the odds ratio for adult obesity associated with early versus late AR was 6.0 (95% CI, 1.3-26.6).
An early AR is associated with an increased risk of adult obesity independent of parent obesity and the BMI at AR. Future research should examine the biological and behavioral determinants of AR.
Display omitted
•Numerical study of strain and damage sensing in nanocomposite bonded explosives.•Coupled electromechanical peridynamics formulation used in modeling microstructure.•Explicitly ...resolves grains/binder allowing damage in both phases and the interface.•CNT content and grain conductivity significantly affect strain and damage sensing.•Calibrated numerical results are found to compare well with experimental data.
Polymer bonded explosives are complex materials which can weaken and more importantly accidentally detonate as a result of microstructural damage if subjected to mechanical insults. It is proposed that dispersing carbon nanotubes within the material will allow for in situ, real time structural health monitoring owing to the unique piezoresistive properties of nanocomposites. To explore this further, a coupled electromechanical peridynamics framework is employed to investigate the deformation and damage sensing capabilities of nanocomposite bonded explosives at the microstructural level. The peridynamics framework enables in capturing key deformation and damage mechanisms associated with this complex material system. Preliminary studies show that CNT content and the electrical conductivity of the grains are important parameters which impact the piezoresistive response. Moreover, these parameters affect the response in the elastic and damage regimes in significantly different ways. Lastly, results from numerical simulations are compared to experimental data on the piezoresistive response of mock NCBX materials, and it is concluded that there is promise in this novel application of nanocomposite based sensing.
Objectives. To describe the achievement of inactive disease (ID) and remission in polyarticular juvenile idiopathic arthritis (JIA) and to measure the associations among patient characteristics, ...imaging results and these outcomes. Methods. We performed a retrospective cohort study of children with polyarticular JIA diagnosed and treated at Seattle Children's Hospital between 1 January 2000 and 31 December 2006. Each patient's disease status (active disease vs ID) was determined for every clinic visit. Adjusted relative risk estimates were obtained using Mantel–Haenszel methods. Results. One hundred and four children were included. Patients were followed up for an average of 30 months. Patients achieved 138 episodes of ID. Fifty-one patients achieved 69 episodes of clinical remission on medication. When duration of active disease was summed over each patient's follow-up, patients spent a mean of 66.3% of their follow-up with active disease. Patients with evidence of joint damage on imaging studies obtained within 6 months of their first clinic visit spent a mean of 79% of their follow-up with active disease. Patients without these findings spent a mean of 58.5% of their follow-up with active disease (P < 0.001). Children who were RF+ and children with early evidence of joint damage tended to have a higher prevalence of active disease during the follow-up period. Conclusions. In this cohort, children with polyarticular JIA spent the majority of their follow-up with active disease. Because children with early radiographic evidence of joint damage and children who were RF+ tended to have the most active disease, improving outcomes for these subgroups may be an important goal for prospective study.
Abstract
The molar mass of H
2
O (18 g mol
−1
) is smaller than that of dry air (29 g mol
−1
), which makes humid air lighter than dry air with the same temperature and pressure. This vapor buoyancy ...(VB) effect has been traditionally considered small in large-scale climate dynamics and even neglected in some leading climate models. Here, using theory and aquaplanet simulations with prescribed surface temperatures, we show that VB increases tropospheric air temperature, and that the warmer atmosphere emits more clear-sky thermal radiation by about 2–4 W m
−2
in the dry subtropical areas, a significant radiative effect. We then analyze Coupled Model Intercomparison Project Phase 6 simulations with prescribed sea surface temperatures and realistic topography. The results show that VB can increase clear-sky thermal radiation by up to 5 W m
−2
over the ocean and about 15 W m
−2
over the subtropical arid land regions. The radiative effect over arid land is amplified by a substantial increase of surface temperature due to VB. Our results highlight the role of VB in regulating Earth’s energy balance both at the top of the atmosphere and at the land surface. This study points to new ways to improve climate models and their simulated energy balance.
PDF
