Cloud effects have repeatedly been pointed out as the leading source of uncertainty in projections of future climate, yet clouds remain poorly understood and simulated in climate models. Aquaplanets ...provide a simplified framework for comparing and understanding cloud effects, and how they are partitioned as a function of regime, in large-scale models. This work uses two climate models to demonstrate that aquaplanets can successfully predict a climate model’s sensitivity to an idealized climate change. For both models, aquaplanet climate sensitivity is similar to that of the realistic configuration. Tropical low clouds appear to play a leading role in determining the sensitivity. Regions of large-scale subsidence, which cover much of the tropics, are most directly responsible for the differences between the models. Although cloud effects and climate sensitivity are similar for aquaplanets and realistic configurations, the aquaplanets lack persistent stratocumulus in the tropical atmosphere. This, and an additional analysis of the cloud response in the realistically configured simulations, suggests the representation of shallow (trade wind) cumulus convection, which is ubiquitous in the tropics, is largely responsible for differences in the simulated climate sensitivity of these two models.
Klebsiella pneumoniae is a major health threat. Vaccination and passive immunization are considered as alternative therapeutic strategies for managing Klebsiella infections. Lipopolysaccharide O ...antigens are attractive candidates because of the relatively small range of known O-antigen polysaccharide structures, but immunotherapeutic applications require a complete understanding of the structures found in clinical settings. Currently, the precise number of Klebsiella O antigens is unknown because available serological tests have limited resolution, and their association with defined chemical structures is sometimes uncertain. Molecular serotyping methods can evaluate clinical prevalence of O serotypes but require a full understanding of the genetic determinants for each O-antigen structure. This is problematic with Klebsiella pneumoniae because genes outside the main rfb (O-antigen biosynthesis) locus can have profound effects on the final structure. Here, we report two new loci encoding enzymes that modify a conserved polysaccharide backbone comprising disaccharide repeat units →3)-α-d-Galp-(1→3)-β-d-Galf-(1→ (O2a antigen). We identified in serotype O2aeh a three-component system that modifies completed O2a glycan in the periplasm by adding 1,2-linked α-Galp side-group residues. In serotype O2ac, a polysaccharide comprising disaccharide repeat units →5)-β-d-Galf-(1→3)-β-d-GlcpNAc-(1→ (O2c antigen) is attached to the non-reducing termini of O2a-antigen chains. O2c-polysaccharide synthesis is dependent on a locus encoding three glycosyltransferase enzymes. The authentic O2aeh and O2c antigens were recapitulated in recombinant Escherichia coli hosts to establish the essential gene set for their synthesis. These findings now provide a complete understanding of the molecular genetic basis for the known variations in Klebsiella O-antigen carbohydrate structures based on the O2a backbone.
Rett syndrome (RTT) is a severe neurodevelopmental disorder caused, in most classic cases, by mutations in the X-linked methyl-CpG-binding protein 2 gene (
MECP2). A large degree of phenotypic ...variation has been observed in patients with RTT, both those with and without
MECP2 mutations. We describe a family consisting of a proband with a phenotype that showed considerable overlap with that of RTT, her identical twin sister with autistic disorder and mild-to-moderate intellectual disability, and a brother with profound intellectual disability and seizures. No pathogenic
MECP2 mutations were found in this family, and the Xq28 region that contains the
MECP2 gene was not shared by the affected siblings. Three other candidate regions were identified by microsatellite mapping, including 10.3 Mb at Xp22.31-pter between Xpter and
DXS1135, 19.7 Mb at Xp22.12-p22.11 between
DXS1135 and
DXS1214, and 16.4 Mb at Xq21.33 between
DXS1196 and
DXS1191. The
ARX and
CDKL5 genes, both of which are located within the Xp22 region, were sequenced in the affected family members, and a deletion of nucleotide 183 of the coding sequence (c.183delT) was identified in
CDKL5 in the affected family members. In a screen of 44 RTT cases, a single splice-site mutation, IVS13-1G→A, was identified in a girl with a severe phenotype overlapping RTT. In the mouse brain,
Cdkl5 expression overlaps—but is not identical to—that of
Mecp2, and its expression is unaffected by the loss of
Mecp2. These findings confirm
CDKL5 as another locus associated with epilepsy and X-linked mental retardation. These results also suggest that mutations in
CDKL5 can lead to a clinical phenotype that overlaps RTT. However, it remains to be determined whether
CDKL5 mutations are more prevalent in specific clinical subgroups of RTT or in other clinical presentations.
Purpose: We examined positive behavioral resources and characteristics that might distinguish resilient personality prototypes among persons with chronic spinal cord injury/disorder (SCID). Positive ...psychology variables with clear linkages to existing psychological interventions were examined as potential mediators of the resilience-well-being relationship. Research Method and Design: A cross-sectional, self-report study was conducted. Two hundred and ninety-eight consenting members of the Paralyzed Veterans of America (268 male; 236 self-identified as white) provided useable survey data for analysis (including 161 veterans with tetraplegia, 107 with paraplegia, 30 with cauda equina). Cluster analysis of Big Five personality traits identified resilient and nonresilient personality profiles. Tests of mean differences between resilient and nonresilient participants on behavioral resources and characteristics were performed. Path models predicting well-being and health-related quality of life (HRQL) were conducted. Results: One hundred and sixty-three respondents had resilient personality profiles and 135 had nonresilient profiles. Resilient individuals reported significantly more optimal scores on every positive psychology variable, and greater well-being and HRQL than nonresilient respondents. Path models found the relationship of resilience to well-being was explained through its beneficial associations with psychological flexibility, use of personal strengths, meaning in life (MIL), and gratitude. Psychological flexibility also mediated the resilience-HRQL relationship. Cauda equina was significantly associated with higher pain interference and lower HRQL. Conclusions: Higher gratitude, MIL, use of personal strengths, and psychological flexibility appear to characterize resilience and well-being among persons with chronic SCID. Further studies are needed to understand the impact of pain interference on HRQL among individuals with cauda equina.
Impact and Implications
The present study documents several positive behavioral resources and characteristics that typify resilience among persons with chronic spinal cord injury/disorder. The results should prompt rehabilitation psychologists to consider further study of the positive psychology variables examined in this paper, and the potential use of the existing interventions associated with each one.
Ischemia/reperfusion (I/R) injury elicits damage to mitochondria. Antioxidants provide protection from I/R-induced mitochondrial damage. The goal of this study was to determine the impact of ...mitochondria-specific overexpression of
GPx4 (PHGPx) on cardiac function following I/R. Transgenic mice were created in which PHGPx was overexpressed solely in the mitochondrion (mPHGPx). MPHGPx and littermate control hearts were subjected to global no-flow ischemia (20 min) followed by reflow reperfusion (30, 60, and 90 min). Following I/R, mPHGPx hearts possessed significantly better rates of contraction, developed pressures, and peak-systolic pressures as compared to controls (
P
<
0.05). No differences were observed in rates of relaxation or end-diastolic pressures. Lipid peroxidation was significantly lower in mitochondria from mPHGPx hearts as compared to controls, following I/R (
P
<
0.05). Electron transport chain (ETC) complex I, III, and IV activities were significantly higher in mPHGPx hearts as compared to controls, following I/R (
P
<
0.05). MPHGPx overexpression enhanced ETC complex I, III, and IV activities in subsarcolemmal mitochondria (SSM;
P
<
0.05), and ETC complex I and III activities in interfibrillar mitochondria (IFM;
P
<
0.05) following I/R. These results indicate that mitochondria-specific
GPx4 overexpression protects cardiac contractile function and preserves ETC complex activities following I/R. These results provide further rationale for the use of mPHGPx as a therapeutic protectant.
Abstract Numerical weather, climate, or Earth system models involve the coupling of components. At a broad level, these components can be classified as the resolved fluid dynamics, unresolved fluid ...dynamical aspects (i.e., those represented by physical parameterizations such as subgrid-scale mixing), and nonfluid dynamical aspects such as radiation and microphysical processes. Typically, each component is developed, at least initially, independently. Once development is mature, the components are coupled to deliver a model of the required complexity. The implementation of the coupling can have a significant impact on the model. As the error associated with each component decreases, the errors introduced by the coupling will eventually dominate. Hence, any improvement in one of the components is unlikely to improve the performance of the overall system. The challenges associated with combining the components to create a coherent model are here termed physics–dynamics coupling. The issue goes beyond the coupling between the parameterizations and the resolved fluid dynamics. This paper highlights recent progress and some of the current challenges. It focuses on three objectives: to illustrate the phenomenology of the coupling problem with references to examples in the literature, to show how the problem can be analyzed, and to create awareness of the issue across the disciplines and specializations. The topics addressed are different ways of advancing full models in time, approaches to understanding the role of the coupling and evaluation of approaches, coupling ocean and atmosphere models, thermodynamic compatibility between model components, and emerging issues such as those that arise as model resolutions increase and/or models use variable resolutions.
The metabolic stress placed on skeletal muscle by aerobic exercise promotes acute and long-term health benefits in part through changes in gene expression. However, the transducers that mediate ...altered gene expression signatures have not been completely elucidated. Regulated in development and DNA damage 1 (REDD1) is a stress-induced protein whose expression is transiently increased in skeletal muscle following acute aerobic exercise. However, the role of this induction remains unclear. Because REDD1 altered gene expression in other model systems, we sought to determine whether REDD1 induction following acute exercise altered the gene expression signature in muscle. To do this, wild-type and REDD1-null mice were randomized to remain sedentary or undergo a bout of acute treadmill exercise. Exercised mice recovered for 1, 3, or 6 h before euthanization. Acute exercise induced a transient increase in REDD1 protein expression within the plantaris only at 1 h postexercise, and the induction occurred in both cytosolic and nuclear fractions. At this time point, global changes in gene expression were surveyed using microarray. REDD1 induction was required for the exercise-induced change in expression of 24 genes. Validation by RT-PCR confirmed that the exercise-mediated changes in genes related to exercise capacity, muscle protein metabolism, neuromuscular junction remodeling, and Metformin action were negated in REDD1-null mice. Finally, the exercise-mediated induction of REDD1 was partially dependent upon glucocorticoid receptor activation. In all, these data show that REDD1 induction regulates the exercise-mediated change in a distinct set of genes within skeletal muscle.
Over the past decade, the number of open-ocean gauges capable of parsing information about a passing tsunami has steadily increased, particularly through national cable networks and international ...buoyed efforts such as the Deep-ocean Assessment and Reporting of Tsunami (DART). This information is analyzed to disseminate tsunami warnings to affected regions. However, most current warnings that incorporate tsunami are directed at mid- and far-field localities. In this study, we analyze the region surrounding four seismically active subduction zones, Cascadia, Japan, Chile, and Java, for their potential to facilitate local tsunami early warning using such systems. We assess which locations currently have instrumentation in the right locations for direct tsunami observations with enough time to provide useful warning to the nearest affected coastline—and which are poorly suited for such systems. Our primary findings are that while some regions are ill-suited for this type of early warning, such as the coastlines of Chile, other localities, like Java, Indonesia, could incorporate direct tsunami observations into their hazard forecasts with enough lead time to be effective for coastal community emergency response. We take into account the effect of tsunami propagation with regard to shallow bathymetry on the fore-arc as well as the effect of earthquake source placement. While it is impossible to account for every type of off-shore tsunamigenic event in these locales, this study aims to characterize a typical large tsunamigenic event occurring in the shallow part of the megathrust as a guide in what is feasible with early tsunami warning.
Colorectal cancers are one of the most prevalent tumour types worldwide and, despite the emergence of targeted and biologic therapies, have among the highest mortality rates. The Personalized ...OncoGenomics (POG) program at BC Cancer performs whole genome and transcriptome analysis (WGTA) to identify specific alterations in an individual's cancer that may be most effectively targeted. Informed using WGTA, a patient with advanced mismatch repair-deficient colorectal cancer was treated with the antihypertensive drug irbesartan and experienced a profound and durable response. We describe the subsequent relapse of this patient and potential mechanisms of response using WGTA and multiplex immunohistochemistry (m-IHC) profiling of biopsies before and after treatment from the same metastatic site of the L3 spine. We did not observe marked differences in the genomic landscape before and after treatment. Analyses revealed an increase in immune signalling and infiltrating immune cells, particularly CD8+ T cells, in the relapsed tumour. These results indicate that the observed anti-tumour response to irbesartan may have been due to an activated immune response. Determining whether there may be other cancer contexts in which irbesartan may be similarly valuable will require additional studies.
A new version of the Community Atmosphere Model (CAM) has been developed and released to the climate community. CAM Version 3 (CAM3) is an atmospheric general circulation model that includes the ...Community Land Model (CLM3), an optional slab ocean model, and a thermodynamic sea ice model. The dynamics and physics in CAM3 have been changed substantially compared to implementations in previous versions. CAM3 includes options for Eulerian spectral, semi-Lagrangian, and finite-volume formulations of the dynamical equations. It supports coupled simulations using either finite-volume or Eulerian dynamics through an explicit set of adjustable parameters governing the model time step, cloud parameterizations, and condensation processes. The model includes major modifications to the parameterizations of moist processes, radiation processes, and aerosols. These changes have improved several aspects of the simulated climate, including more realistic tropical tropopause temperatures, boreal winter land surface temperatures, surface insolation, and clear-sky surface radiation in polar regions. The variation of cloud radiative forcing during ENSO events exhibits much better agreement with satellite observations. Despite these improvements, several systematic biases reduce the fidelity of the simulations. These biases include underestimation of tropical variability, errors in tropical oceanic surface fluxes, underestimation of implied ocean heat transport in the Southern Hemisphere, excessive surface stress in the storm tracks, and offsets in the 500-mb height field and the Aleutian low.
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