The leaf ionome as a multivariable system to detect a plant's physiological status

The contention that quantitative profiles of biomolecules contain information about the physiological state of the organism has motivated a variety of high-throughput molecular profiling experiments. However, unbiased discovery and validation of biomolecular signatures from these experiments remains a challenge. Here we show that the Arabidopsis thaliana (Arabidopsis) leaf ionome, or elemental composition, contains such signatures, and we establish statistical models that connect these multivariable signatures to defined physiological responses, such as iron (Fe) and phosphorus (P) homeostasis. Iron is essential for plant growth and development, but potentially toxic at elevated levels. Because of this, shoot Fe concentrations are tightly regulated and show little variation over a range of Fe concentrations in the environment, making them a poor probe of a plant's Fe status. By evaluating the shoot ionome in plants grown under different Fe nutritional conditions, we have established a multivariable ionomic signature for the Fe response status of Arabidopsis. This signature has been validated against known Fe-response proteins and allows the high-throughput detection of the Fe status of plants with a false negative/positive rate of 18%/16%. A “metascreen” of previously collected ionomic data from 880 Arabidopsis mutants and natural accessions for this Fe response signature successfully identified the known Fe mutants frd1 and frd3. A similar approach has also been taken to identify and use a shoot ionomic signature associated with P homeostasis. This study establishes that multivariable ionomic signatures of physiological states associated with mineral nutrient homeostasis do exist in Arabidopsis and are in principle robust enough to detect specific physiological responses to environmental or genetic perturbations.     

Does the agglomeration effect occur in the hospital sector? The impact of agglomeration economies on the financial performance of hospitals—An evidence from Poland

The main aim of the article is to analyze the occurrence of agglomeration effect in the hospital sector on the basis of financial performance. The considerations are made on the example of hospitals in Poland—the country that survived the latest economic crisis relatively well, usually generating positive values of GDP, but where still there is an ongoing discussion on the final shape of healthcare financing model. The article is based on the assumption that there occur significant differences in financial performance between hospitals according to their location. The research hypothesis is as follows: Hospitals operating in big cities are featured by better financial condition than their counterparts operating in smaller towns. To verify the hypothesis, the methods of financial analysis and statistical hypothesis testing are used. As it is emphasized in the article, the assumption is true and the hypothesis can be verified positively.     

Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation

Activation of CD4⁺ T cells results in rapid proliferation and differentiation into effector and regulatory subsets. CD4⁺ effector T cell (Teff) (Th1 and Th17) and Treg subsets are metabolically distinct, yet the specific metabolic differences that modify T cell populations are uncertain. Here, we evaluated CD4⁺ T cell populations in murine models and determined that inflammatory Teffs maintain high expression of glycolytic genes and rely on high glycolytic rates, while Tregs are oxidative and require mitochondrial electron transport to proliferate, differentiate, and survive. Metabolic profiling revealed that pyruvate dehydrogenase (PDH) is a key bifurcation point between T cell glycolytic and oxidative metabolism. PDH function is inhibited by PDH kinases (PDHKs). PDHK1 was expressed in Th17 cells, but not Th1 cells, and at low levels in Tregs, and inhibition or knockdown of PDHK1 selectively suppressed Th17 cells and increased Tregs. This alteration in the CD4⁺ T cell populations was mediated in part through ROS, as N-acetyl cysteine (NAC) treatment restored Th17 cell generation. Moreover, inhibition of PDHK1 modulated immunity and protected animals against experimental autoimmune encephalomyelitis, decreasing Th17 cells and increasing Tregs. Together, these data show that CD4⁺ subsets utilize and require distinct metabolic programs that can be targeted to control specific T cell populations in autoimmune and inflammatory diseases.     

Tests of calibration and goodness‐of‐fit in the survival setting

To access the calibration of a predictive model in a survival analysis setting, several authors have extended the Hosmer–Lemeshow goodness‐of‐fit test to survival data. Grønnesby and Borgan developed a test under the proportional hazards assumption, and Nam and D'Agostino developed a nonparametric test that is applicable in a more general survival setting for data with limited censoring. We analyze the performance of the two tests and show that the Grønnesby–Borgan test attains appropriate size in a variety of settings, whereas the Nam‐D'Agostino method has a higher than nominal Type 1 error when there is more than trivial censoring. Both tests are sensitive to small cell sizes. We develop a modification of the Nam‐D'Agostino test to allow for higher censoring rates. We show that this modified Nam‐D'Agostino test has appropriate control of Type 1 error and comparable power to the Grønnesby–Borgan test and is applicable to settings other than proportional hazards. We also discuss the application to small cell sizes. Copyright © 2015 John Wiley & Sons, Ltd.     

Altered modulation of gamma oscillation frequency by speed of visual motion in children with autism spectrum disorders

Background

Recent studies link autism spectrum disorders (ASD) with an altered balance between excitation and inhibition (E/I balance) in cortical networks. The brain oscillations in high gamma-band (50–120 Hz) are sensitive to the E/I balance and may appear useful biomarkers of certain ASD subtypes. The frequency of gamma oscillations is mediated by level of excitation of the fast-spiking inhibitory basket cells recruited by increasing strength of excitatory input. Therefore, the experimental manipulations affecting gamma frequency may throw light on inhibitory networks dysfunction in ASD.

Methods

Here, we used magnetoencephalography (MEG) to investigate modulation of visual gamma oscillation frequency by speed of drifting annular gratings (1.2, 3.6, 6.0 °/s) in 21 boys with ASD and 26 typically developing boys aged 7–15 years. Multitaper method was used for analysis of spectra of gamma power change upon stimulus presentation and permutation test was applied for statistical comparisons. We also assessed in our participants visual orientation discrimination thresholds, which are thought to depend on excitability of inhibitory networks in the visual cortex.

Results

Although frequency of the oscillatory gamma response increased with increasing velocity of visual motion in both groups of participants, the velocity effect was reduced in a substantial proportion of children with ASD. The range of velocity-related gamma frequency modulation correlated inversely with the ability to discriminate oblique line orientation in the ASD group, while no such correlation has been observed in the group of typically developing participants.

Conclusions

Our findings suggest that abnormal velocity-related gamma frequency modulation in ASD may constitute a potential biomarker for reduced excitability of fast-spiking inhibitory neurons in a subset of children with ASD.

Electronic supplementary material

The online version of this article (doi:10.1186/s11689-015-9121-x) contains supplementary material, which is available to authorized users.