Humor and preschoolers’ trust: Sensitivity to changing intentions

This research demonstrates that preschoolers (a) avoid trusting informants with humorous intentions when learning novel information and (b) flexibly consider current intentions rather than initial intentions when determining who to trust. In Study 1 (N = 61), 3- and 4-year-olds based their trust on intentions or intentional cues alone, trusting a sincere informant over a joker, even when no prior accuracy or inaccuracy was displayed. In Study 2 (N = 32), 3- and 4-year-olds flexibly based their trust on the informants’ current intentions or intentional cues rather than their initial ones. Children trusted a sincere informant, who originally joked, over a joker, who was originally sincere. In Study 3 (N = 89), 3-, 4-, and 5-year-olds tracked changing intentions, and not just intentional cues, in determining who to trust. Children trusted an informant who joked during training trials but was sincere during test trials over an informant who was ignorant during training trials and was sincere during test trials. However, if the ignorant informant became knowledgeable and the joker continued to joke, the pattern reversed. This is the first study to show that preschoolers consider intentions to joke when learning information. This is also the first study to show that preschoolers do not see trust as stable but rather see it as a function of changing intentions

Rearranging the centromere of the human Y chromosome with φC31 integrase

We have investigated the ability of the integrase from the Streptomyces φC31 ‘phage to either delete or invert 1 Mb of DNA around the centromere of the human Y chromosome in chicken DT40 hybrid somatic cells. Reciprocal and conservative site-specific recombination was observed in 54% of cells expressing the integrase. The sites failed to recombine in the remaining cells because the sites had been damaged. The sequences of the damaged sites indicated that the damage arose as a result of repair of recombination intermediates by host cell pathways. The liability of recombination intermediates to damage is consistent with what is known about the mechanism of serine recombinase reactions. The structures of the products of the chromosome rearrangements were consistent with the published sequence of the Y chromosome indicating that the assembly of the highly repeated region between the sites is accurate to a resolution of about 50 kb. Mini-chromosomes lacking a centromere were not recovered which also suggested that neo-centromere formation occurs infrequently in vertebrate somatic cells. No ectopic recombination was observed between a φC31 integrase attB site and the chicken genome

Preventing axonal sodium overload or mitochondrial calcium uptake protects axonal mitochondria from oxidative stress-induced alterations

In neuroinflammatory and neurodegenerative disorders such as multiple sclerosis, mitochondrial damage caused by oxidative stress is believed to contribute to neuroaxonal damage. Previously, we demonstrated that exposure to hydrogen peroxide (H(2)O(2)) alters mitochondrial morphology and motility in myelinated axons and that these changes initiate at the nodes of Ranvier, where numerous sodium channels are located. Therefore, we suggested that mitochondrial damage may lead to ATP deficit, thereby affecting the efficiency of the sodium-potassium ATPase and eventually leading to sodium overload in axons. The increased intra-axonal sodium may revert the axonal sodium-calcium exchangers and thus may lead to a pathological calcium overload in the axoplasm and mitochondria. Here, we used the explanted murine ventral spinal roots to investigate whether modulation of sodium or calcium influx may prevent mitochondrial alterations in myelinated axons during exogenous application of H(2)O(2) inducing oxidative stress. For that, tetrodotoxin, an inhibitor of voltage-gated sodium ion channels, and ruthenium 360, an inhibitor of the mitochondrial calcium uniporter, were applied simultaneously with hydrogen peroxide to axons. Mitochondrial shape and motility were analyzed. We showed that inhibition of axonal sodium influx prevented oxidative stress-induced morphological changes (i.e., increase in circularity and area and decrease in length) and preserved mitochondrial membrane potential, which is crucial for ATP production. Blocking mitochondrial calcium uptake prevented decrease in mitochondrial motility and also preserved membrane potential. Our findings indicate that alterations of both mitochondrial morphology and motility in the contexts of oxidative stress can be counterbalanced by modulating intramitochondrial ion concentrations pharmacologically. Moreover, motile mitochondria show preserved membrane potentials, pointing to a close association between mitochondrial motility and functionality

Trajectories of self-rated health in people with diabetes: Associations with functioning in a prospective community sample

© 2013 Schmitz et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Self-rated health (SRH) is a single-item measure that is one of the most widely used measures of general health in population health research. Relatively little is known about changes and the trajectories of SRH in people with chronic medical conditions. The aims of the present study were to identify and describe longitudinal trajectories of self-rated health (SRH) status in people with diabetes. Methods: A prospective community study was carried out between 2008 and 2011. SRH was assessed at baseline and yearly at follow-ups (n=1288). Analysis was carried out through trajectory modeling. The trajectory groups were subsequently compared at 4 years follow-up with respect to functioning. Results: Four distinct trajectories of SRH were identified: 1) 72.2% of the participants were assigned to a persistently good SRH trajectory; 2) 10.1% were assigned to a persistently poor SRH trajectory; 3) mean SRH scores changed from good to poor for one group (7.3%); while 4) mean SRH scores changed from poor to medium/good for another group (10.4%). Those with a persistently poor perception of health status were at higher risk for poor functioning at 4 years follow-up than those whose SRH scores decreased from good to poor. Conclusions: SRH is an important predictor for poor functioning in diabetes, but the trajectory of SRH seems to be even more important. Health professionals should pay attention to not only SRH per se, but also changes in SRH over time.This work was supported by Operating Grant MOP-84574 from the Canadian Institutes of Health Research (CIHR). GG was supported by a doctoral fellowship from the CIHR. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

The wheat SnRK1α family and its contribution to Fusarium toxin tolerance.

Deoxynivalenol (DON) is a mycotoxin produced by phytopathogenic Fusarium fungi in cereal grain and plays a role as a disease virulence factor. TaFROG (Triticum aestivum Fusarium Resistance Orphan Gene) enhances wheat resistance to DON and it interacts with a sucrose non-fermenting-1 (SNF1)-related protein kinase 1 catalytic subunit α (SnRK1α). This protein kinase family is central integrator of stress and energy signaling, regulating plant metabolism and growth. Little is known regarding the role of SnRK1α in the biotic stress response, especially in wheat. In this study, 15 wheat (Triticum aestivum) SnRK1α genes (TaSnRK1αs) belonging to four homoeologous groups were identified in the wheat genome. TaSnRK1αs are expressed ubiquitously in all organs and developmental stages apart from two members predominantly detected in grain. While DON treatment had either no effect or downregulated the transcription of TaSnRK1αs, it increased both the kinase activity associated with SnRK1α and the level of active (phosphorylated) SnRK1α. Down-regulation of two TaSnRK1αs homoeolog groups using virus induced gene silencing (VIGS) increased the DON-induced damage of wheat spikelets. Thus, we demonstrate that TaSnRK1αs contribute positively to wheat tolerance of DON and conclude that this gene family may provide useful tools for the improvement of crop biotic stress resistance

Estimation of the correlation coefficient using the Bayesian Approach and its applications for epidemiologic research

BACKGROUND: The Bayesian approach is one alternative for estimating correlation coefficients in which knowledge from previous studies is incorporated to improve estimation. The purpose of this paper is to illustrate the utility of the Bayesian approach for estimating correlations using prior knowledge. METHODS: The use of the hyperbolic tangent transformation (ρ = tanh ξ and r = tanh z) enables the investigator to take advantage of the conjugate properties of the normal distribution, which are expressed by combining correlation coefficients from different studies. CONCLUSIONS: One of the strengths of the proposed method is that the calculations are simple but the accuracy is maintained. Like meta-analysis, it can be seen as a method to combine different correlations from different studies

Teriflunomide preserves neuronal activity and protects mitochondria in brain slices exposed to oxidative stress

Teriflunomide (TFN) limits relapses in relapsing–remitting multiple sclerosis (RRMS) by reducing lymphocytic proliferation through the inhibition of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH) and the subsequent modulation of de novo pyrimidine synthesis. Alterations of mitochondrial function as a consequence of oxidative stress have been reported during neuroinflammation. Previously, we showed that TFN prevents alterations of mitochondrial motility caused by oxidative stress in peripheral axons. Here, we aimed to validate TFN effects on mitochondria and neuronal activity in hippocampal brain slices, in which cellular distribution and synaptic circuits are largely preserved. TFN effects on metabolism and neuronal activity were investigated by assessing oxygen partial pressure and local field potential in acute slices. Additionally, we imaged mitochondria in brain slices from the transgenic Thy1-CFP/COX8A)S2Lich/J (mitoCFP) mice using two-photon microscopy. Although TFN could not prevent oxidative stress-related depletion of ATP, it preserved oxygen consumption and neuronal activity in CNS tissue during oxidative stress. Furthermore, TFN prevented mitochondrial shortening and fragmentation of puncta-shaped and network mitochondria during oxidative stress. Regarding motility, TFN accentuated the decrease in mitochondrial displacement and increase in speed observed during oxidative stress. Importantly, these effects were not associated with neuronal viability and did not lead to axonal damage. In conclusion, during conditions of oxidative stress, TFN preserves the functionality of neurons and prevents morphological and motility alterations of mitochondria

Modifying the m6A brain methylome by ALKBH5-mediated demethylation: a new contender for synaptic tagging

Synaptic plasticity processes, which underlie learning and memory formation, require RNA to be translated local to synapses. The synaptic tagging hypothesis has previously been proposed to explain how mRNAs are available at specific activated synapses. However how RNA is regulated, and which transcripts are silenced or processed as part of the tagging process is still unknown. Modification of RNA by N6-methyladenosine (m6A/m) influences the cellular fate of mRNA. Here, by advanced microscopy, we showed that m6A demethylation by the eraser protein ALKBH5 occurs at active synaptic ribosomes and at synapses during short term plasticity. We demonstrated that at activated glutamatergic post-synaptic sites, both the YTHDF1 and YTHDF3 reader and the ALKBH5 eraser proteins increase in co-localisation to m6A-modified RNAs; but only the readers showed high co-localisation to modified RNAs during late-stage plasticity. The YTHDF1 and YTHFDF3 readers also exhibited differential roles during synaptic maturation suggesting that temporal and subcellular abundance may determine specific function. m6A-sequencing of human parahippocampus brain tissue revealed distinct white and grey matter m6A methylome profiles indicating that cellular context is a fundamental factor dictating regulated pathways. However, in both neuronal and glial cell-rich tissue, m6A effector proteins are themselves modified and m6A epitranscriptional and posttranslational modification processes coregulate protein cascades. We hypothesise that the availability m6A effector protein machinery in conjunction with RNA modification, may be important in the formation of condensed synaptic nanodomain assemblies through liquid-liquid phase separation. Our findings support that m6A demethylation by ALKBH5 is an intrinsic component of the synaptic tagging hypothesis and a molecular switch which leads to alterations in the RNA methylome, synaptic dysfunction and potentially reversible disease states

First insights into the phylogenetic diversity of Mycobacterium tuberculosis in Nepal

BACKGROUND: Tuberculosis (TB) is a major public health problem in Nepal. Strain variation in Mycobacterium tuberculosis may influence the outcome of TB infection and disease. To date, the phylogenetic diversity of M. tuberculosis in Nepal is unknown. METHODS AND FINDINGS: We analyzed 261 M. tuberculosis isolates recovered from pulmonary TB patients recruited between August 2009 and August 2010 in Nepal. M. tuberculosis lineages were determined by single nucleotide polymorphisms (SNP) typing and spoligotyping. Drug resistance was determined by sequencing the hot spot regions of the relevant target genes. Overall, 164 (62.8%) TB patients were new, and 97 (37.2%) were previously treated. Any drug resistance was detected in 50 (19.2%) isolates, and 16 (6.1%) were multidrug-resistant. The most frequent M. tuberculosis lineage was Lineage 3 (CAS/Delhi) with 106 isolates (40.6%), followed by Lineage 2 (East-Asian lineage, includes Beijing genotype) with 84 isolates (32.2%), Lineage 4 (Euro-American lineage) with 41 (15.7%) isolates, and Lineage 1 (Indo-Oceanic lineage) with 30 isolates (11.5%). Based on spoligotyping, we found 45 different spoligotyping patterns that were previously described. The Beijing (83 isolates, 31.8%) and CAS spoligotype (52, 19.9%) were the dominant spoligotypes. A total of 36 (13.8%) isolates could not be assigned to any known spoligotyping pattern. Lineage 2 was associated with female sex (adjusted odds ratio [aOR] 2.58, 95% confidence interval [95% CI] 1.42-4.67, p = 0.002), and any drug resistance (aOR 2.79; 95% CI 1.43-5.45; p = 0.002). We found no evidence for an association of Lineage 2 with age or BCG vaccination status. CONCLUSIONS: We found a large genetic diversity of M. tuberculosis in Nepal with representation of all four major lineages. Lineages 3 and 2 were dominating. Lineage 2 was associated with clinical characteristics. This study fills an important gap on the map of the M. tuberculosis genetic diversity in the Asian reg

Gfi1aa and Gfi1b set the pace for primitive erythroblast differentiation from hemangioblasts in the zebrafish embryo

The transcriptional repressors G fi 1(a) and G fi 1b are epigenetic regulators with unique and overlapping roles in hematopoiesis. In different contexts, G fi 1 and G fi 1b restrict or promote cell proliferation, prevent apoptosis, in fl uence cell fate decisions, and are essential for terminal differentiation. Here, we show in primitive red blood cells (prRBCs) that they can also set the pace for cellular differentiation. In zebra fi sh, prRBCs express 2 of 3 zebra fi sh G fi 1/ 1bparalogs,G fi 1aaandG fi 1b.Therecentlyidenti fi edzebra fi sh gfi1aa gene trap allele qmc551 drives erythroid green fl uorescent protein (GFP) instead of G fi 1aa expression, yet homozygous carriers have normal prRBCs. prRBCs display a maturation defect only after splice morpholino-mediated knockdown of G fi 1b in gfi1aa qmc551 homozygous embryos. To study the transcriptome of the G fi 1aa/1b double-depleted cells, we performed an RNA-Seq experi- ment on GFP-positive prRBCs sorted from 20-h our-old embryos that were heterozygous or homozygous for gfi1aa qmc551 ,aswellas wt or morphant for gfi1b .Wesubsequentlycon fi rmed and extended these data in whole-mount in situ hybridization experiments on newly generated single- and double-mutant embryos. Combi ned, the data showed that in the absence of G fi 1aa, the synchronously developing prRBCs were delayed in activating late erythr oid differentiation, as they struggled to suppress early erythroid and endothelial transcripti on programs. The latter highlighted the bipotent natu re of the progenitors from which prRBCs arise. In the absence of G fi 1aa, G fi 1b promoted erythroid differentiation as stepwise loss of wt gfi1b copies progressively delayed G fi 1aa-depleted prRBCs even further, showing that G fi 1aa and G fi 1b together set the pace for prRBC diffe rentiation from hemangioblasts