807 research outputs found
Toxoplasma effectors targeting host signaling and transcription
Early electron microscopy studies revealed the elaborate cellular features that define the unique adaptations of apicomplexan parasites. Among these were bulbous rhoptry (ROP) organelles and small, dense granules (GRAs), both of which are secreted during invasion of host cells. These early morphological studies were followed by the exploration of the cellular contents of these secretory organelles, revealing them to be comprised of highly divergent protein families with few conserved domains or predicted functions. In parallel, studies on host-pathogen interactions identified many host signaling pathways that were mysteriously altered by infection. It was only with the advent of forward and reverse genetic strategies that the connections between individual parasite effectors and the specific host pathways that they targeted finally became clear. The current repertoire of parasite effectors includes ROP kinases and pseudokinases that are secreted during invasion and that block host immune pathways. Similarly, many secretory GRA proteins alter host gene expression by activating host transcription factors, through modification of chromatin, or by inducing small noncoding RNAs. These effectors highlight novel mechanisms by whichhas learned to harness host signaling to favor intracellular survival and will guide future studies designed to uncover the additional complexity of this intricate host-pathogen interaction
Ecosystem heterogeneity and diversity mitigate Amazon forest resilience to frequent extreme droughts
© 2018 The Authors. New Phytologist © 2018 New Phytologist Trust The impact of increases in drought frequency on the Amazon forest's composition, structure and functioning remain uncertain. We used a process- and individual-based ecosystem model (ED2) to quantify the forest's vulnerability to increased drought recurrence. We generated meteorologically realistic, drier-than-observed rainfall scenarios for two Amazon forest sites, Paracou (wetter) and Tapajós (drier), to evaluate the impacts of more frequent droughts on forest biomass, structure and composition. The wet site was insensitive to the tested scenarios, whereas at the dry site biomass declined when average rainfall reduction exceeded 15%, due to high mortality of large-sized evergreen trees. Biomass losses persisted when year-long drought recurrence was shorter than 2–7 yr, depending upon soil texture and leaf phenology. From the site-level scenario results, we developed regionally applicable metrics to quantify the Amazon forest's climatological proximity to rainfall regimes likely to cause biomass loss > 20% in 50 yr according to ED2 predictions. Nearly 25% (1.8 million km2) of the Amazon forests could experience frequent droughts and biomass loss if mean annual rainfall or interannual variability changed by 2σ. At least 10% of the high-emission climate projections (CMIP5/RCP8.5 models) predict critically dry regimes over 25% of the Amazon forest area by 2100
Regulatory control and the costs and benefits of biochemical noise
Experiments in recent years have vividly demonstrated that gene expression
can be highly stochastic. How protein concentration fluctuations affect the
growth rate of a population of cells, is, however, a wide open question. We
present a mathematical model that makes it possible to quantify the effect of
protein concentration fluctuations on the growth rate of a population of
genetically identical cells. The model predicts that the population's growth
rate depends on how the growth rate of a single cell varies with protein
concentration, the variance of the protein concentration fluctuations, and the
correlation time of these fluctuations. The model also predicts that when the
average concentration of a protein is close to the value that maximizes the
growth rate, fluctuations in its concentration always reduce the growth rate.
However, when the average protein concentration deviates sufficiently from the
optimal level, fluctuations can enhance the growth rate of the population, even
when the growth rate of a cell depends linearly on the protein concentration.
The model also shows that the ensemble or population average of a quantity,
such as the average protein expression level or its variance, is in general not
equal to its time average as obtained from tracing a single cell and its
descendants. We apply our model to perform a cost-benefit analysis of gene
regulatory control. Our analysis predicts that the optimal expression level of
a gene regulatory protein is determined by the trade-off between the cost of
synthesizing the regulatory protein and the benefit of minimizing the
fluctuations in the expression of its target gene. We discuss possible
experiments that could test our predictions.Comment: Revised manuscript;35 pages, 4 figures, REVTeX4; to appear in PLoS
Computational Biolog
Functional traits and phenotypic plasticity modulate species coexistence across contrasting climatic conditions
Functional traits are expected to modulate plant competitive dynamics. However, how traits
and their plasticity in response to contrasting environments connect with the mechanisms
determining species coexistence remains poorly understood. Here, we couple field experiments
under two contrasting climatic conditions to a plant population model describing
competitive dynamics between 10 annual plant species in order to evaluate how 19 functional
traits, covering physiological, morphological and reproductive characteristics, are associated
with species’ niche and fitness differences. We find a rich diversity of univariate and multidimensional
associations, which highlight the primary role of traits related to water- and lightuse-
efficiency for modulating the determinants of competitive outcomes. Importantly, such
traits and their plasticity promote species coexistence across climatic conditions by enhancing
stabilizing niche differences and by generating competitive trade-offs between species.
Our study represents a significant advance showing how leading dimensions of plant function
connect to the mechanisms determining the maintenance of biodiversity
Haemoglobin mass and running time trial performance after recombinant human erythropoietin administration in trained men
<p>Recombinant human erythropoietin (rHuEpo) increases haemoglobin mass (Hbmass) and maximal oxygen uptake (v˙ O2 max).</p>
<p>Purpose: This study defined the time course of changes in Hbmass, v˙ O2 max as well as running time trial performance
following 4 weeks of rHuEpo administration to determine whether the laboratory observations would translate into actual
improvements in running performance in the field.</p>
<p>Methods: 19 trained men received rHuEpo injections of 50 IUNkg21 body mass every two days for 4 weeks. Hbmass was
determined weekly using the optimized carbon monoxide rebreathing method until 4 weeks after administration. v˙ O2 max
and 3,000 m time trial performance were measured pre, post administration and at the end of the study.</p>
<p>Results: Relative to baseline, running performance significantly improved by ,6% after administration (10:3061:07 min:sec
vs. 11:0861:15 min:sec, p,0.001) and remained significantly enhanced by ,3% 4 weeks after administration
(10:4661:13 min:sec, p,0.001), while v˙ O2 max was also significantly increased post administration
(60.765.8 mLNmin21Nkg21 vs. 56.066.2 mLNmin21Nkg21, p,0.001) and remained significantly increased 4 weeks after
rHuEpo (58.065.6 mLNmin21Nkg21, p = 0.021). Hbmass was significantly increased at the end of administration compared to
baseline (15.261.5 gNkg21 vs. 12.761.2 gNkg21, p,0.001). The rate of decrease in Hbmass toward baseline values post
rHuEpo was similar to that of the increase during administration (20.53 gNkg21Nwk21, 95% confidence interval (CI) (20.68,
20.38) vs. 0.54 gNkg21Nwk21, CI (0.46, 0.63)) but Hbmass was still significantly elevated 4 weeks after administration
compared to baseline (13.761.1 gNkg21, p<0.001).</p>
<p>Conclusion: Running performance was improved following 4 weeks of rHuEpo and remained elevated 4 weeks after
administration compared to baseline. These field performance effects coincided with rHuEpo-induced elevated v˙ O2 max and
Hbmass.</p>
The Goldbeter-Koshland switch in the first-order region and its response to dynamic disorder
In their classical work (Proc. Natl. Acad. Sci. USA, 1981, 78:6840-6844),
Goldbeter and Koshland mathematically analyzed a reversible covalent
modification system which is highly sensitive to the concentration of
effectors. Its signal-response curve appears sigmoidal, constituting a
biochemical switch. However, the switch behavior only emerges in the
"zero-order region", i.e. when the signal molecule concentration is much lower
than that of the substrate it modifies. In this work we showed that the
switching behavior can also occur under comparable concentrations of signals
and substrates, provided that the signal molecules catalyze the modification
reaction in cooperation. We also studied the effect of dynamic disorders on the
proposed biochemical switch, in which the enzymatic reaction rates, instead of
constant, appear as stochastic functions of time. We showed that the system is
robust to dynamic disorder at bulk concentration. But if the dynamic disorder
is quasi-static, large fluctuations of the switch response behavior may be
observed at low concentrations. Such fluctuation is relevant to many biological
functions. It can be reduced by either increasing the conformation
interconversion rate of the protein, or correlating the enzymatic reaction
rates in the network.Comment: 23 pages, 4 figures, accepted by PLOS ON
Belowground DNA-based techniques: untangling the network of plant root interactions
Contains fulltext :
91591.pdf (publisher's version ) (Closed access)7 p
Statistical Inference for Valued-Edge Networks: Generalized Exponential Random Graph Models
Across the sciences, the statistical analysis of networks is central to the
production of knowledge on relational phenomena. Because of their ability to
model the structural generation of networks, exponential random graph models
are a ubiquitous means of analysis. However, they are limited by an inability
to model networks with valued edges. We solve this problem by introducing a
class of generalized exponential random graph models capable of modeling
networks whose edges are valued, thus greatly expanding the scope of networks
applied researchers can subject to statistical analysis
Endomicroscopic and transcriptomic analysis of impaired barrier function and malabsorption in environmental enteropathy
Introduction: Environmental enteropathy (EE) is associated with growth failure, micronutrient malabsorption and impaired responses to oral vaccines. We set out to define cellular mechanisms of impaired barrier function in EE and explore protective mechanisms. Methods: We studied 49 adults with environmental enteropathy in Lusaka, Zambia using confocal laser endomicroscopy (CLE); histology, immunohistochemistry and mRNA sequencing of small intestinal biopsies; and correlated these with plasma lipopolysaccharide (LPS) and a zinc uptake test. Results: CLE images (median 134 for each study) showed virtually ubiquitous small intestinal damage. Epithelial defects, imaged by histology and claudin 4 immunostaining, were predominantly seen at the tips of villi and corresponded with leakage imaged in vivo by CLE. In multivariate analysis, circulating log-transformed LPS was correlated with cell shedding events (β = 0.83; P = 0.035) and with serum glucagon-like peptide-2 (β = -0.13; P = 0.007). Zinc uptake from a test dose of 25mg was attenuated in 30/47 (64%) individuals and in multivariate analysis was reduced by HIV, but positively correlated with GLP-2 (β = 2.72; P = 0.03). There was a U-shaped relationship between circulating LPS and villus surface area. Transcriptomic analysis identified 23 differentially expressed genes in severe enteropathy, including protective peptides and proteins. Conclusions: Confocal endomicroscopy, claudin 4 immunostaining and histology identify epithelial defects which are probably sites of bacterial translocation, in the presence of which increased epithelial surface area increases the burden of translocation. GLP 2 and other protective peptides may play an important role in mucosal protection in EE
Does clinical equipoise apply to cluster randomized trials in health research?
This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, Weijer and colleagues set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the third of the questions posed, namely, does clinical equipoise apply to CRTs in health research? The ethical principle of beneficence is the moral obligation not to harm needlessly and, when possible, to promote the welfare of research subjects. Two related ethical problems have been discussed in the CRT literature. First, are control groups that receive only usual care unduly disadvantaged? Second, when accumulating data suggests the superiority of one intervention in a trial, is there an ethical obligation to act
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