There are thousands of known cellular phosphorylation sites, but the paucity of ways to identify kinases for particular phosphorylation events remains a major roadblock for understanding kinase ...signaling. To address this, we here develop a generally applicable method that exploits the large number of kinase inhibitors that have been profiled on near-kinome-wide panels of protein kinases. The inhibition profile for each kinase provides a fingerprint that allows identification of unknown kinases acting on target phosphosites in cell extracts. We validate the method on diverse known kinase-phosphosite pairs, including histone kinases, EGFR autophosphorylation, and Integrin β1 phosphorylation by Src-family kinases. We also use our approach to identify the previously unknown kinases responsible for phosphorylation of INCENP at a site within a commonly phosphorylated motif in mitosis (a non-canonical target of Cyclin B-Cdk1), and of BCL9L at S915 (PKA). We show that the method has clear advantages over in silico and genetic screening.
Context. L1630 in the Orion B molecular cloud, which includes the iconic Horsehead Nebula, illuminated by the star system σ Ori, is an example of a photodissociation region (PDR). In PDRs, stellar ...radiation impinges on the surface of dense material, often a molecular cloud, thereby inducing a complex network of chemical reactions and physical processes. Aims. Observations toward L1630 allow us to study the interplay between stellar radiation and a molecular cloud under relatively benign conditions, that is, intermediate densities and an intermediate UV radiation field. Contrary to the well-studied Orion Molecular Cloud 1 (OMC1), which hosts much harsher conditions, L1630 has little star formation. Our goal is to relate the C ii fine-structure line emission to the physical conditions predominant in L1630 and compare it to studies of OMC1. Methods. The C ii 158 μm line emission of L1630 around the Horsehead Nebula, an area of 12′ × 17′, was observed using the upgraded German Receiver for Astronomy at Terahertz Frequencies (upGREAT) onboard the Stratospheric Observatory for Infrared Astronomy (SOFIA). Results. Of the C ii emission from the mapped area 95%, 13 L⊙, originates from the molecular cloud; the adjacent H ii region contributes only 5%, that is, 1 L⊙. From comparison with other data (CO (1 − 0)-line emission, far-infrared (FIR) continuum studies, emission from polycyclic aromatic hydrocarbons (PAHs)), we infer a gas density of the molecular cloud of nH ~ 3 × 103 cm-3, with surface layers, including the Horsehead Nebula, having a density of up to nH ~ 4 × 104 cm-3. The temperature of the surface gas is T ~ 100 K. The average C ii cooling efficiency within the molecular cloud is 1.3 × 10-2. The fraction of the mass of the molecular cloud within the studied area that is traced by C ii is only 8%. Our PDR models are able to reproduce the FIR-C ii correlations and also the CO (1 − 0)-C ii correlations. Finally, we compare our results on the heating efficiency of the gas with theoretical studies of photoelectric heating by PAHs, clusters of PAHs, and very small grains, and find the heating efficiency to be lower than theoretically predicted, a continuation of the trend set by other observations. Conclusions. In L1630 only a small fraction of the gas mass is traced by C ii. Most of the C ii emission in the mapped area stems from PDR surfaces. The layered edge-on structure of the molecular cloud and limitations in spatial resolution put constraints on our ability to relate different tracers to each other and to the physical conditions. From our study, we conclude that the relation between C ii emission and physical conditions is likely to be more complicated than often assumed. The theoretical heating efficiency is higher than the one we calculate from the observed C ii emission in the L1630 molecular cloud.
1 Center for Human Nutrition, 2 Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, and 3 Department of Pediatrics, University of Colorado Health Sciences Center, Denver, ...Colorado 80262; and 4 Department of Medicine, University of Vermont, Burlington, Vermont 05405
Submitted 9 July 2004
; accepted in final form 23 August 2004
Metabolic adjustments occur with weight loss that may contribute to a high rate of weight regain. We have previously observed in obesity-prone, obese rats that weight reduction is accompanied by a suppression in resting metabolic rate beyond what would be predicted for the change in metabolic mass. In the present study, we examine if this adjustment in metabolic efficiency is affected by the length of time in weight maintenance and if it contributes to the propensity to regain after weight loss. Twenty-four-hour, nonresting, and resting energy expenditure (REE) were obtained by indirect calorimetry and normalized to metabolic mass estimated by dual-energy X-ray absorptiometry. A 10% loss in body weight in weight-reduced rats was accompanied by a 15% suppression in adjusted REE. This enhancement in metabolic efficiency was not altered with either 8 or 16 wk of weight maintenance, but it did resolve when the forced control of intake was removed and the weight was regained. The rate of weight regain increased with the time in weight maintenance and was exceptionally high early during the relapse period. During this high rate of weight gain, the suppression in REE persists while consumption increases to a level that is higher than when they were obese. In summary, an enhanced metabolic efficiency and an elevated appetite both contribute (60% and 40%, respectively) to a large potential energy imbalance that, when the forcible control of energy intake is relieved, becomes actualized and results in an exceptionally high rate of weight regain.
weight maintenance; energy balance; body composition; indirect calorimetry
Address for reprint requests and other correspondence: P. S. MacLean, Univ. of Colorado Health Sciences Center, Center for Human Nutrition, 4200 E. 9th Ave., C225, Denver, CO 80262 (E-mail: paul.maclean{at}uchsc.edu )
The flexible fiberoptic bronchoscope (FOB) is viewed as the gold standard device for awake intubation in the difficult airway. The newer rigid flexible laryngoscope (RIFL) was developed for similar ...indications. In this study we compare these two devices for management of potentially difficult airways after induction of general anesthesia.
Adult surgical patients requiring endotracheal intubation and having a predicted difficult airway based on airway examination, BMI≥35, and/or history of prior difficult intubation were randomized to undergo endotracheal intubation with either the RIFL or FOB. Induction was performed in usual manner, and intubation was performed by providers proficient with both airway devices after induction of general anesthesia. The primary outcomes measured were intubation success, time to intubation, number of attempts, and the need for airway assist maneuvers. The lowest observed oxygen saturation and airway trauma were also recorded.
A total of 41 patients were enrolled, with 20 randomized to each group and 1 withdrawal. Intubation was successful in all patients with both devices. The median time for successful intubation was significantly shorter in the RIFL group compared to the FOB group (49 vs. 64 seconds; P=0.048). Airway assist maneuvers were required in 2 (10%) intubations with the RIFL compared to 16 (80%) intubations with the FOB (P<0.001). There were no significant differences in lowest oxygen saturation or airway trauma.
The RIFL required significantly less time and fewer airway assist maneuvers for successful endotracheal intubation compared to FOB when used by experienced providers in patients with anticipated difficult airways.
Summary
Background
Antibodies against tumour necrosis factor‐alpha (anti‐TNF) are effective therapies in the treatment of ulcerative colitis (UC), but their comparative efficacy is unknown.
Aim
To ...perform a network meta‐analysis comparing the efficacy of anti‐TNF agents in UC.
Methods
After screening 506 studies, reviewers extracted information on seven studies. Traditional meta‐analysis (TMA) was used to compare each anti‐TNF agent to placebo. Bayesian network meta‐analysis (NMA) was performed to compare the effects of anti‐TNF agents to placebo. In addition, sample sizes for comparative efficacy trials were calculated.
Results
Compared to placebo, TMA revealed that anti‐TNF agents result in a higher likelihood of induction of remission and response (RR: 2.45, 95% CI: 1.72–3.47 and RR: 1.65, 95% CI: 1.37–1.99 respectively) as well as maintenance of remission and response (RR: 2.00, 95% CI: 1.52–2.62 and RR: 1.76, 95% CI: 1.46–2.14 respectively). Individually, infliximab, adalimumab and goliumumab resulted in a higher likelihood of induction and maintenance for both remission and response. NMA found nonsignificant trends in comparisons of the individual agents. The required sample sizes for direct head‐to‐head trials between infliximab and adalimumab for induction and maintenance are 174 and 204 subjects respectively.
Conclusions
This study demonstrates that, compared to placebo, infliximab, adalimumab and golimumab are all effective for the induction and maintenance of remission in ulcerative colitis. However, network meta‐analysis demonstrates that no single agent is clinically superior to the others and therefore, other factors such as cost, safety, route of administration and patient preference should dictate our choice of anti‐TNF agents. A randomised comparative efficacy trial between infliximab and adalimumab in UC is of practical size and should be performed.
Perfluorochemicals (PFCs) are the subject of increasingly intense environmental research. Despite their detection both in biota and in aqueous systems, little attention has been paid to the possible ...presence of this class of compounds in solid environmental matrixes. The limited available data indicate that some PFCs such as perfluorooctane sulfonate (PFOS) may strongly sorb to solids, and sewage sludge is widely suspected as a major sink of PFCs entering municipal waste streams. A quantitative analytical method was developed that consists of liquid solvent extraction of the analytes from sediments and sludge, cleanup via solid-phase extraction, and injection of the extracts with internal standards into a high-performance liquid chromatography (HPLC) system coupled to a tandem mass spectrometer (LC/MS/MS). The limits of detections of the method were analyte and matrix dependent, but ranged from 0.7 to 2.2 ng/g and 0.041 to 0.246 ng/g (dry weight) for sludge and sediment, respectively. A demonstration of the method was performed by conducting a limited survey of domestic sludge and sediments. The concentration of PFCs in domestic sludge ranged from 5 to 152 ng/g for total perfluorocarboxylates and 55 to 3370 ng/g for total perfluoroalkyl sulfonyl-based chemicals. Data from a survey of San Francisco Bay Area sediments suggest widespread occurrence of PFCs in sediments at the low ng/g to sub-ng/g level. Furthermore, substances that may be transformed to PFOS, such as 2-(N-ethylperfluorooctanesulfonamido) acetic acid (N-EtFOSAA) and 2-(N-methylperfluorooctanesulfonamido) acetic acid (N-MeFOSAA), are present in both sediments and sludge at levels often exceeding PFOS.
Pictorial health warnings on sugar-sweetened beverages (SSBs) are a promising policy for preventing diet-related disease in children. A recent study found that pictorial warnings reduced parents' ...purchases of SSBs for their children by 17%. However, the psychological mechanisms through which warnings affect parental behavior remain unknown. We aimed to identify the mechanisms that explain how pictorial warnings affect parents' SSB purchasing behavior for their children using secondary data from a randomized trial.
In 2020-2021, parents of children ages 2 to 12 years (n = 325) completed a shopping task in a convenience store laboratory in North Carolina, USA. Participants were randomly assigned to a pictorial warnings arm (SSBs displayed pictorial health warnings about type 2 diabetes and heart damage) or a control arm (SSBs displayed a barcode label). Parents then bought a beverage for their child and took a survey measuring 11 potential psychological mediators, selected based on health behavior theories and a model explaining the impact of tobacco warnings. We conducted simple mediation analyses to identify which of the 11 mechanisms mediated the impact of exposure to pictorial warnings on purchasing any SSBs for their children.
Two of the 11 constructs were statistically significant mediators. First, the impact of pictorial warnings on the likelihood of purchasing any SSB was mediated by parents' perceptions that SSBs were healthier for their child (mediated effect= -0.17; 95% CI = - 0.33, - 0.05). Second, parents' intentions to serve SSBs to their children also mediated the effect of warnings on likelihood of purchasing any SSB (mediated effect= -0.07, 95% CI=-0.21, - 0.003).
Pictorial warnings reduced parents' purchases of SSBs for their children by making parents think SSBs are less healthful for their children and reducing their intentions to serve SSBs to their children. Communication approaches that target healthfulness perceptions and intentions to serve SSBs may motivate parents to buy fewer SSBs for their children.
This report summarises a workshop convened by ILSI Europe on 3 and 4 April 2017 to discuss the issue of dietary sweetness. The objectives were to understand the roles of sweetness in the diet, ...establish whether exposure to sweetness affects diet quality and energy intake, and consider whether sweetness per se affects health. Although there may be evidence for tracking of intake of some sweet components of the diet through childhood, evidence for tracking of whole diet sweetness, or through other stages of maturity are lacking. The evidence to date does not support adverse effects of sweetness on diet quality or energy intake, except where sweet food choices increase intake of free sugars. There is some evidence for improvements in diet quality and reduced energy intake where sweetness without calories replaces sweetness with calories. There is a need to understand the physiological and metabolic relevance of sweet taste receptors on the tongue, in the gut and elsewhere in the body, as well as possible differentiation in the effects of sustained consumption of individual sweeteners. Despite a plethora of studies, there is no consistent evidence for an association of sweetness sensitivity/preference with obesity or type 2 diabetes. A multifaceted integrated approach, characterising nutritive and sensory aspects of the whole diet or dietary patterns, may be more valuable in providing contextual insight. The outcomes of the workshop could be used as a scientific basis to inform the expert community and create more useful dialogue among health care professionals.
The two deep ice cores recovered by the GRIP and GISP2 projects at Summit, Greenland, agree in detail over the past 100,000 years and demonstrate dramatic climate variability in the North Atlantic ...region during the last glacial, before the current period of Holocene stability. This glacial climate instability has subsequently been documented in the marine sedimentary record of surface-ocean conditions in the North Atlantic. Before 100 kyr ago the two ice core records are discrepant, however, casting doubt on whether the oxygen isotope fluctuations during the last interglacial (Eemian) seen in the GRIP core represent a true climate signal. Here we present high-resolution records of foraminiferal assemblages and ice-rafted detritus from two North Atlantic cores for the interval 65 kyr to 135 kyr ago, extending the surface-ocean record back to the Eemian. The correlation between our records and the Greenland ice-core records is good throughout the period in which the two ice cores agree, suggesting a regionally coherent climate response. During the Eemian, our marine records show a more stable climate than that implied by the GRIP ice core, suggesting that localized phenomena may be responsible for the variability in the latter record during the Eemian.
Almost 60 years ago Dicke introduced the term superradiance to describe a signature quantum effect: N atoms can collectively emit light at a rate proportional to N(2). Structures that superradiate ...must also have enhanced absorption, but the former always dominates in natural systems. Here we show that this restriction can be overcome by combining several well-established quantum control techniques. Our analytical and numerical calculations show that superabsorption can then be achieved and sustained in certain simple nanostructures, by trapping the system in a highly excited state through transition rate engineering. This opens the prospect of a new class of quantum nanotechnology with potential applications including photon detection and light-based power transmission. An array of quantum dots or a molecular ring structure could provide a suitable platform for an experimental demonstration.
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![[C II] emission from L1630 ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0004-6361_1432-0746/small "[C II] emission from L1630 in the Orion B molecular cloud")
