Identifying Neural Drivers with Functional MRI: An Electrophysiological Validation

Whether functional magnetic resonance imaging (fMRI) allows the identification of neural drivers remains an open question of particular importance to refine physiological and neuropsychological models of the brain, and/or to understand neurophysiopathology. Here, in a rat model of absence epilepsy showing spontaneous spike-and-wave discharges originating from the first somatosensory cortex (S1BF), we performed simultaneous electroencephalographic (EEG) and fMRI measurements, and subsequent intracerebral EEG (iEEG) recordings in regions strongly activated in fMRI (S1BF, thalamus, and striatum). fMRI connectivity was determined from fMRI time series directly and from hidden state variables using a measure of Granger causality and Dynamic Causal Modelling that relates synaptic activity to fMRI. fMRI connectivity was compared to directed functional coupling estimated from iEEG using asymmetry in generalised synchronisation metrics. The neural driver of spike-and-wave discharges was estimated in S1BF from iEEG, and from fMRI only when hemodynamic effects were explicitly removed. Functional connectivity analysis applied directly on fMRI signals failed because hemodynamics varied between regions, rendering temporal precedence irrelevant. This paper provides the first experimental substantiation of the theoretical possibility to improve interregional coupling estimation from hidden neural states of fMRI. As such, it has important implications for future studies on brain connectivity using functional neuroimaging.     

Cutting the forest to see a single tree?

The development of single-molecule tools has significantly impacted the way we think about biochemical processes. Watching a single protein in action allows us to observe kinetic details and rare subpopulations that are hidden in ensemble-averaging techniques. I will discuss here the pros and cons of the single-molecule approach in studying ligand binding in macromolecular systems and how these techniques can be applied to characterize the behavior of large multicomponent biochemical systems.     

Characteristics of human intestinal Escherichia coli with changing environments

To investigate if the characteristics of human intestinal Escherichia coli are changing with the environment of the host, we studied intestinal E. coli from subjects having recently migrated from a temperate to a tropical area. We determined the phylogenetic group, the prevalence of the antibiotic resistance, the presence of integrons and the strain diversity in faecal isolates from 25 subjects originally from metropolitan France and expatriated to French Guyana. These characteristics were compared with those of 25 previously studied Wayampi Amerindian natives of French Guyana and from 25 metropolitan French residents. The three groups of subjects were matched for age and sex, had not taken antibiotics for at least 1 month, nor had been hospitalized within the past year. In all, the characteristics of intestinal E. coli from Expatriates were intermediate between those found in residents from metropolitan France and those found in natives of French Guyana. Prevalence of carriage of resistant Gram-negative bacteria in Expatriates was intermediate between French residents and Wayampi as were the prevalence of integrons in E. coli (12.3% versus 16.3% and 7.8% respectively), and the intra-host diversity of E. coli (2.3 strains/subject versus 1.9 and 3.1, respectively); lastly, in Expatriates, the prevalence of carriage of phylogenetic group B2 strains was lower than in French residents (16% versus 56%, P  = 0.005), while carriage of phylogenetic group A strains was lower than in Wayampi (56% versus 88%, P  = 0.03). Our results suggest that the composition of the commensal intestinal flora of humans is not static but changes dynamically in response to new environmental conditions.     

Regulation of the neural circuitry of emotion by compassion meditation: effects of meditative expertise

Recent brain imaging studies using functional magnetic resonance imaging (fMRI) have implicated insula and anterior cingulate cortices in the empathic response to another's pain. However, virtually nothing is known about the impact of the voluntary generation of compassion on this network. To investigate these questions we assessed brain activity using fMRI while novice and expert meditation practitioners generated a loving-kindness-compassion meditation state. To probe affective reactivity, we presented emotional and neutral sounds during the meditation and comparison periods. Our main hypothesis was that the concern for others cultivated during this form of meditation enhances affective processing, in particular in response to sounds of distress, and that this response to emotional sounds is modulated by the degree of meditation training. The presentation of the emotional sounds was associated with increased pupil diameter and activation of limbic regions (insula and cingulate cortices) during meditation (versus rest). During meditation, activation in insula was greater during presentation of negative sounds than positive or neutral sounds in expert than it was in novice meditators. The strength of activation in insula was also associated with self-reported intensity of the meditation for both groups. These results support the role of the limbic circuitry in emotion sharing. The comparison between meditation vs. rest states between experts and novices also showed increased activation in amygdala, right temporo-parietal junction (TPJ), and right posterior superior temporal sulcus (pSTS) in response to all sounds, suggesting, greater detection of the emotional sounds, and enhanced mentation in response to emotional human vocalizations for experts than novices during meditation. Together these data indicate that the mental expertise to cultivate positive emotion alters the activation of circuitries previously linked to empathy and theory of mind in response to emotional stimuli.     

Promoter DNA hypermethylation and gene repression in undifferentiated Arabidopsis cells

Maintaining and acquiring the pluripotent cell state in plants is critical to tissue regeneration and vegetative multiplication. Histone-based epigenetic mechanisms are important for regulating this undifferentiated state. Here we report the use of genetic and pharmacological experimental approaches to show that Arabidopsis cell suspensions and calluses specifically repress some genes as a result of promoter DNA hypermethylation. We found that promoters of the MAPK12, GSTU10 and BXL1 genes become hypermethylated in callus cells and that hypermethylation also affects the TTG1, GSTF5, SUVH8, fimbrin and CCD7 genes in cell suspensions. Promoter hypermethylation in undifferentiated cells was associated with histone hypoacetylation and primarily occurred at CpG sites. Accordingly, we found that the process specifically depends on MET1 and DRM2 methyltransferases, as demonstrated with DNA methyltransferase mutants. Our results suggest that promoter DNA methylation may be another important epigenetic mechanism for the establishment and/or maintenance of the undifferentiated state in plant cells.     

Chemical Variability of Ivoirian Xylopia rubescens Leaf Oil

Forty‐two essential oil samples were isolated from leaves of Xylopia rubescens harvested in three forests of Southern Ivory Coast. All the samples have been submitted to GC‐FID and the retention indices (RIs) of individual components have been measured on two capillary columns of different polarity. In addition, 20 oil samples, selected on the basis of their chromatographic profile, were also analyzed by ¹³C‐NMR and 24 components (78.0 – 92.4% of the whole compositions) have been identified. The content of the main components varied drastically from sample to sample: furanoguaia‐1,4‐diene (5.7 – 54.1%), furanoguaia‐1,3‐diene (1.1 – 10.5%), (8Z,11Z,14Z)‐heptadeca‐8,11,14‐trien‐2‐one (4.3 – 16.0%), and (E)‐β‐caryophyllene (1.7 – 17.3%). Hierarchical cluster and principal components analysis of the 42 oil compositions allowed the distinction of two well‐differentiated groups of unequal importance within the oil samples. Oil samples of the main group (Group II) contained mainly furanoguaia‐1,4‐diene (mean [M] = 43.1%; standard deviation [SD] = 3.2%) while furanoguaia‐1,3‐diene (M = 8.4%; SD = 0.9%) and (8Z,11Z,14Z)‐heptadeca‐8,11,14‐trien‐2‐one (M = 7.1%; SD = 1.5%) were present at appreciable contents. The composition of Group I was dominated by furanoguaia‐1,4‐diene (M = 17.0%; SD = 8.5%), (8Z,11Z,14Z)‐heptadeca‐8,11,14‐trien‐2‐one (M = 10.2%; SD = 2.4%) and (E)‐β‐caryophyllene (M = 9.5%; SD = 5.3%).     

Improving carbon and energy distribution by coupling growth and medium chain length polyhydroxyalkanoate production from fatty acids by <Emphasis Type="Italic">Pseudomonas putida</Emphasis> KT2440

The production of medium chain length polyhydroxyalkanoates by Pseudomonas putida KT2440 from fatty acids leads to the loss of a large proportion of carbon. We studied the possibility of a shift of potentially available energy and carbon towards monitored residual growth during the production phase. A Fed-Batch culture achieving 125.6 g/L of total biomass containing 54.4% (g/g) of medium chain length polyhydroxyalkanoates was carried out leading to an overall experimental carbon yield of 0.7 Cmole/Cmole. The analysis of modeling fluxes deduced from experimental data indicated how carbon and reduced cofactors (NADH and FADH₂) were managed to conclude that part of the carbon and reduced cofactors made available by polymer production were used in anabolic pathways. The strategy which consisted in coupled growth and medium chain length polyhydroxyalkanoate production enhanced the global yields compared to growth followed by a production phase. The understanding of carbon and energy fluxes distribution allowed deducing optimized culture strategy to perform the highest reported in the literature.     

A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat

Context: There is an ongoing search for specific and translational biomarkers of drug-induced liver injury (DILI). MicroRNA-122 (miR-122) has previously shown potential as a sensitive, specific, and translational biomarker of DILI in both rodent, and human studies.

Objective: To build on previous work within the field, we examined biomarker kinetics in a rat model of acetaminophen (APAP)-induced liver injury to confirm the sensitivity, and specificity of miR-122 and glutamate dehydrogenase (GLDH).

Materials and methods: qRT-PCR and a standard enzymatic assay were used for biomarker analysis.

Results: Both miR-122 and GLDH were demonstrated to be more readily-detectable biomarkers of APAP-DILI than alanine aminotransferase (ALT). Peak levels for all biomarkers were detected at 2 days after APAP. At day 3, miR-122 had returned to baseline; however, other biomarkers remained elevated between 3 and 4 days. We were also able to demonstrate that, although miR-122 is present in greater quantities in exosome-free form, both exosome-bound and non-vesicle bound miR-122 are released in a similar profile throughout the course of DILI.

Discussion and conclusions: Together, this study demonstrates that both GLDH and miR-122 could be used during preclinical drug-development as complementary biomarkers to ALT to increase the chance of early detection of hepatotoxicity.