Executive Function and IQ Predict Mathematical and Attention Problems in Very Preterm Children

Objective of this study was to examine the impact of executive function (EF) on mathematical and attention problems in very preterm (gestational age ≤ 30 weeks) children. Participants were 200 very preterm (mean age 8.2 ± 2.5 years) and 230 term children (mean age 8.3 ± 2.3 years) without severe disabilities, born between 1996 and 2004. EFs assessed included verbal fluency, verbal working memory, visuospatial span, planning, and impulse control. Mathematics was assessed with the Dutch Pupil Monitoring System and parents and teachers rated attention problems using standardized behavior questionnaires. The impact of EF was calculated over and above processing speed indices and IQ. Interactions with group (very preterm versus term birth status) were examined. Analyses were conducted separately for two subsamples: children in preschool and children in primary school. Very preterm children performed poorer on tests for mathematics and had more parent and teacher rated attention problems than term controls (ß_s>.11, P_s<.01). IQ contributed unique variance to mathematics in preschool and in primary school (ß_s>.16, P_s<.007). A significant interaction of group with IQ (ß = −. 24, P = .02) showed that IQ contributed unique variance to attention problems as rated by teachers, but that effects were stronger for very preterm than for term infants. Over and above IQ, EF contributed unique variance to mathematics in primary school (ß = .13, P<.001), to parent rated inattention in preschool and in primary school (ß_s>−.16, P_s<.04), and to teacher rated inattention in primary school (ß = −.19; ß = .19, P_s<.009). In conclusion, impaired EF is, over and above impaired IQ, an important predictor for poor mathematics and attention problems following very preterm birth.     

Variable Behavior of iPSCs Derived from CML Patients for Response to TKI and Hematopoietic Differentiation

Chronic myeloid leukemia disease (CML) found effective therapy by treating patients with tyrosine kinase inhibitors (TKI), which suppress the BCR-ABL1 oncogene activity. However, the majority of patients achieving remission with TKI still have molecular evidences of disease persistence. Various mechanisms have been proposed to explain the disease persistence and recurrence. One of the hypotheses is that the primitive leukemic stem cells (LSCs) can survive in the presence of TKI. Understanding the mechanisms leading to TKI resistance of the LSCs in CML is a critical issue but is limited by availability of cells from patients. We generated induced pluripotent stem cells (iPSCs) derived from CD34⁺ blood cells isolated from CML patients (CML-iPSCs) as a model for studying LSCs survival in the presence of TKI and the mechanisms supporting TKI resistance. Interestingly, CML-iPSCs resisted to TKI treatment and their survival did not depend on BCR-ABL1, as for primitive LSCs. Induction of hematopoietic differentiation of CML-iPSC clones was reduced compared to normal clones. Hematopoietic progenitors obtained from iPSCs partially recovered TKI sensitivity. Notably, different CML-iPSCs obtained from the same CML patients were heterogeneous, in terms of BCR-ABL1 level and proliferation. Thus, several clones of CML-iPSCs are a powerful model to decipher all the mechanisms leading to LSC survival following TKI therapy and are a promising tool for testing new therapeutic agents.     

Noise-Induced Inner Hair Cell Ribbon Loss Disturbs Central Arc Mobilization: A Novel Molecular Paradigm for Understanding Tinnitus

Increasing evidence shows that hearing loss is a risk factor for tinnitus and hyperacusis. Although both often coincide, a causal relationship between tinnitus and hyperacusis has not been shown. Currently, tinnitus and hyperacusis are assumed to be caused by elevated responsiveness in subcortical circuits. We examined both the impact of different degrees of cochlear damage and the influence of stress priming on tinnitus induction. We used (1) a behavioral animal model for tinnitus designed to minimize stress, (2) ribbon synapses in inner hair cells (IHCs) as a measure for deafferentation, (3) the integrity of auditory brainstem responses (ABR) to detect differences in stimulus-evoked neuronal activity, (4) the expression of the activity-regulated cytoskeletal protein, Arc, to identify long-lasting changes in network activity within the basolateral amygdala (BLA), hippocampal CA1, and auditory cortex (AC), and (5) stress priming to investigate the influence of corticosteroid on trauma-induced brain responses. We observed that IHC ribbon loss (deafferentation) leads to tinnitus when ABR functions remain reduced and Arc is not mobilized in the hippocampal CA1 and AC. If, however, ABR waves are functionally restored and Arc is mobilized, tinnitus does not occur. Both central response patterns were found to be independent of a profound threshold loss and could be shifted by the corticosterone level at the time of trauma. We, therefore, discuss the findings in the context of a history of stress that can trigger either an adaptive or nonadaptive brain response following injury.     

Role of Glycoside Phosphorylases in Mannose Foraging by Human Gut Bacteria

To metabolize both dietary fiber constituent carbohydrates and host glycans lining the intestinal epithelium, gut bacteria produce a wide range of carbohydrate-active enzymes, of which glycoside hydrolases are the main components. In this study, we describe the ability of phosphorylases to participate in the breakdown of human N-glycans, from an analysis of the substrate specificity of UhgbMP, a mannoside phosphorylase of the GH130 protein family discovered by functional metagenomics. UhgbMP is found to phosphorolyze β-d-Manp-1,4-β-d-GlcpNAc-1,4-d-GlcpNAc and is also a highly efficient enzyme to catalyze the synthesis of this precious N-glycan core oligosaccharide by reverse phosphorolysis. Analysis of sequence conservation within family GH130, mapped on a three-dimensional model of UhgbMP and supported by site-directed mutagenesis results, revealed two GH130 subfamilies and allowed the identification of key residues responsible for catalysis and substrate specificity. The analysis of the genomic context of 65 known GH130 sequences belonging to human gut bacteria indicates that the enzymes of the GH130_1 subfamily would be involved in mannan catabolism, whereas the enzymes belonging to the GH130_2 subfamily would rather work in synergy with glycoside hydrolases of the GH92 and GH18 families in the breakdown of N-glycans. The use of GH130 inhibitors as therapeutic agents or functional foods could thus be considered as an innovative strategy to inhibit N-glycan degradation, with the ultimate goal of protecting, or restoring, the epithelial barrier.     

Short-term temperature impact on soil heterotrophic respiration in limed agricultural soil samples

This study sought to investigate the hourly and daily timescale responses of soil CO₂ fluxes to temperature in a limed agricultural soil. Observations from different incubation experiments were compared with the results of a model combining biotic (heterotrophic respiration) and abiotic (carbonate weathering) components. Several samples were pre-incubated for 8–9 days at three temperatures (5, 15 and 25 °C) and then submitted to short-term temperature (STT) cycles (where the temperature was increased from 5 to 35 °C in 10 °C stages, with each stage being 3 h long). During the temperature cycles (hourly timescale), the soil CO₂ fluxes increased significantly with temperature under all pre-incubation temperature (PIT) treatments. A hysteresis effect and negative fluxes during cooling phases were also systematically observed. At a given hourly timescale temperature, there was a negative relationship of the CO₂ fluxes with the PIT. Using the combined model allowed the experimental results to be clearly described, including the negative fluxes and the hysteresis effect, showing the potentially large contribution of abiotic fluxes to total fluxes in limed soils, after STT changes. The fairly good agreement between the measured and simulated flux results also suggested that the biotic flux temperature sensitivity was probably unaffected by timescale (hourly or daily) or PIT. The negative relationship of the CO₂ fluxes with the PIT probably derived from very labile soil carbon depletion, as shown in the simulations. This was not, however, confirmed by soil carbon measurements, which leaves open the possibility of adaptation within the microbial community.     

Analysis of Allele-Specific Expression in Mouse Liver by RNA-Seq: A Comparison With Cis-eQTL Identified Using Genetic Linkage

We report an analysis of allele-specific expression (ASE) and parent-of-origin expression in adult mouse liver using next generation sequencing (RNA-Seq) of reciprocal crosses of heterozygous F₁ mice from the parental strains C57BL/6J and DBA/2J. We found a 60% overlap between genes exhibiting ASE and putative cis-acting expression quantitative trait loci (cis-eQTL) identified in an intercross between the same strains. We discuss the various biological and technical factors that contribute to the differences. We also identify genes exhibiting parental imprinting and complex expression patterns. Our study demonstrates the importance of biological replicates to limit the number of false positives with RNA-Seq data.