The aged hematopoietic system promotes hippocampal‐dependent cognitive decline

The aged systemic milieu promotes cellular and cognitive impairments in the hippocampus. Here, we report that aging of the hematopoietic system directly contributes to the pro‐aging effects of old blood on cognition. Using a heterochronic hematopoietic stem cell (HSC) transplantation model (in which the blood of young mice is reconstituted with old HSCs), we find that exposure to an old hematopoietic system inhibits hippocampal neurogenesis, decreases synaptic marker expression, and impairs cognition. We identify a number of factors elevated in the blood of young mice reconstituted with old HSCs, of which cyclophilin A (CyPA) acts as a pro‐aging factor. Increased systemic levels of CyPA impair cognition in young mice, while inhibition of CyPA in aged mice improves cognition. Together, these data identify age‐related changes in the hematopoietic system as drivers of hippocampal aging.     

Microbial Growth and Carbon Use Efficiency in the Rhizosphere and Root-Free Soil

Plant-microbial interactions alter C and N balance in the rhizosphere and affect the microbial carbon use efficiency (CUE)–the fundamental characteristic of microbial metabolism. Estimation of CUE in microbial hotspots with high dynamics of activity and changes of microbial physiological state from dormancy to activity is a challenge in soil microbiology. We analyzed respiratory activity, microbial DNA content and CUE by manipulation the C and nutrients availability in the soil under Beta vulgaris. All measurements were done in root-free and rhizosphere soil under steady-state conditions and during microbial growth induced by addition of glucose. Microorganisms in the rhizosphere and root-free soil differed in their CUE dynamics due to varying time delays between respiration burst and DNA increase. Constant CUE in an exponentially-growing microbial community in rhizosphere demonstrated the balanced growth. In contrast, the CUE in the root-free soil increased more than three times at the end of exponential growth and was 1.5 times higher than in the rhizosphere. Plants alter the dynamics of microbial CUE by balancing the catabolic and anabolic processes, which were decoupled in the root-free soil. The effects of N and C availability on CUE in rhizosphere and root-free soil are discussed.     

Scheduling data analytics work with performance guarantees: queuing and machine learning models in synergy

In today’s scaled out systems, co-scheduling data analytics work with high priority user workloads is common as it utilizes better the vast hardware availability. User workloads are dominated by periodic patterns, with alternating periods of high and low utilization, creating promising conditions to schedule data analytics work during low activity periods. To this end, we show the effectiveness of machine learning models in accurately predicting user workload intensities, essentially by suggesting the most opportune time to co-schedule data analytics work. Yet, machine learning models cannot predict the effects of performance interference when co-scheduling is employed, as this constitutes a “new” observation. Specifically, in tiered storage systems, their hierarchical design makes performance interference even more complex, thus accurate performance prediction is more challenging. Here, we quantify the unknown performance effects of workload co-scheduling by enhancing machine learning models with queuing theory ones to develop a hybrid approach that can accurately predict performance and guide scheduling decisions in a tiered storage system. Using traces from commercial systems we illustrate that queuing theory and machine learning models can be used in synergy to surpass their respective weaknesses and deliver robust co-scheduling solutions that achieve high performance.     

Advantages of q-PCR as a method of screening for gene targeting in mammalian cells using conventional and whole BAC-based constructs

We evaluate here the use of real-time quantitative PCR (q-PCR) as a method for screening for homologous recombinants generated in mammalian cells from either conventional gene-targeting constructs or whole BAC-based constructs. Using gene-targeted events at different loci, we show that q-PCR is a highly sensitive and accurate method for screening for conventional gene targeting that can reduce the number of clones requiring follow-up screening by Southern blotting. We further compared q-PCR to fluorescent in situ hybridization (FISH) for the detection of gene-targeting events using full-length BAC-based constructs designed to introduce mutations either into one gene or simultaneously into two adjacent genes. We find that although BAC-based constructs appeared to have high rates of homologous recombination when evaluated by FISH, screening by FISH was prone to false positives that were detected by q-PCR. Our results demonstrate the utility of q-PCR as a screening tool for gene targeting and further highlight potential problems with the use of whole BAC-based constructs for homologous recombination.     

Backbone Cyclization of the C-terminal Part of Substance P. Part 1: The Important Role of the Sulphur in Position 11

Novel backbone-to-side chain and backbone-to-backbone cyclic analogues of substance P (SP) were prepared by solid-phase synthesis and screened for biological activity. An analogue containing a thioether- lactam ring between positions 9 and 11 showed an EC₅₀ value of 20nM toward the neurokinin 1 (NK-1) and was inactive toward the NK-2 and NK-3 receptors. On the other hand, in a multiple backbone cyclic peptide library of similar analogues, in which the sulphur was excluded from the ring, very low activity was detected. The activity was re-evaluated and was found to be even lower (EC₅₀=0.11 mM ) than the previously published data. These results indicate that the thioether moiety has a crucial role in receptor activation. The results also show tolerance of the NK-1 receptor, but not NK-2 or NK-3, to cyclization of the C-terminal portion of the SP_6–11 hexapeptide.     

The Futile Cycling of Hexose Phosphates Could Account for the Fact That Hexokinase Exerts a High Control on Glucose Phosphorylation but Not on Glycolytic Rate in Transgenic Potato (Solanum tuberosum) Roots

The metabolism of potato (Solanum tuberosum) roots constitutively over- and underexpressing hexokinase (HK, EC 2.7.1.1) was examined. An 11-fold variation in HK activity resulted in altered root growth, with antisense roots growing better than sense roots. Quantification of sugars, organic acids and amino acids in transgenic roots demonstrated that the manipulation of HK activity had very little effect on the intracellular pools of these metabolites. However, adenylate and free Pi levels were negatively affected by an increase in HK activity. The flux control coefficient of HK over the phosphorylation of glucose was measured for the first time in plants. Its value varied with HK level. It reached 1.71 at or below normal HK activity value and was much lower (0.32) at very high HK levels. Measurements of glycolytic flux and O₂ uptake rates demonstrated that the differences in glucose phosphorylation did not affect significantly glycolytic and respiratory metabolism. We hypothesized that these results could be explained by the existence of a futile cycle between the pools of hexose-Ps and carbohydrates. This view is supported by several lines of evidence. Firstly, activities of enzymes capable of catalyzing these reactions were detected in roots, including a hexose-P phosphatase. Secondly, metabolic tracer experiments using ¹⁴C-glucose as precursor showed the formation of ¹⁴C-fructose and ¹⁴C-sucrose. We conclude that futile cycling of hexose-P could be partially responsible for the differences in energetic status in roots with high and low HK activity and possibly cause the observed alterations in growth in transgenic roots. The involvement of HK and futile cycles in the control of glucose-6P metabolism is discussed.     

Phylogeography of northern Dolly Varden Salvelinus malma malma based on analysis of mitochondrial DNA

The northern Dolly Varden, Salvelinus malma malma, is a typical representative of arctic fauna distributed in northeastern Asia and northwestern North America. Because its spawning habitats were affected by Pleistocene glacial advances over most of its natural range, S. m. malma is among the most interesting objects of phylogeographic and microevolutionary studies. We reconstructed the genealogy of mtDNA haplotypes from 27 Alaskan and Asian populations to study the influence of glacial and geological vicariance events on the contemporary population genetic structure, phylogeographic subdivision and distribution of the northern Dolly Varden. Analysis of restriction site states in three PCR‐amplified mtDNA regions (ND1/ND2, ND5/ND6, Cytb/D‐loop; 47% of the mitochondrial genome) resolved 75 haplotypes in 436 fish. Similar patterns of subspecific variation apparent from hierarchical diversity and nested clade analyses of mtDNA haplotypes identify weak spatial differentiation and low levels of divergence. Our results suggest that (1) demographic history has been influenced by historical range expansions and recent isolation by distance, (2) present populations from Asia and North America were colonized from one main Beringian Refugium, and (3) that this taxon's ancestral population probably experienced a bottleneck in the Beringian Refugium during the late Pleistocene (Wisconsin) glacial period.     

Long ncRNA expression associates with tissue-specific enhancers

Long non-coding RNAs (ncRNA) have recently been demonstrated to be expressed from a subset of enhancers and to be required for the distant regulation of gene expression. Several approaches to predict enhancers have been developed based on various chromatin marks and occupancy of enhancer-binding proteins. Despite the rapid advances in the field, no consensus how to define tissue specific enhancers yet exists. Here, we identify 2,695 long ncRNAs annotated by ENCODE (corresponding to 28% of all ENCODE annotated long ncRNAs) that overlap tissue-specific enhancers. We use a recently developed algorithm to predict tissue-specific enhancers, PreSTIGE, that is based on the H3K4me1 mark and tissue specific expression of mRNAs. The expression of the long ncRNAs overlapping enhancers is significantly higher when the enhancer is predicted as active in a specific cell line, suggesting a general interdependency of active enhancers and expression of long ncRNAs. This dependency is not identified using previous enhancer prediction algorithms that do not account for expression of their downstream targets. The predicted enhancers that overlap annotated long ncRNAs generally have a lower ratio of H3K4me1 to H3K4me3, suggesting that enhancers expressing long ncRNAs might be associated with specific epigenetic marks. In conclusion, we demonstrate the tissue-specific predictive power of PreSTIGE and provide evidence for thousands of long ncRNAs that are expressed from active tissue-specific enhancers, suggesting a particularly important functional relationship between long ncRNAs and enhancer activity in determining tissue-specific gene expression.     

Organic N deposition favours soil C sequestration by decreasing priming effect

Plant and Soil - Understanding seed-soil dynamics is important for improving plant emergence and growth. The objectives of this study were to develop a Seed-Soil model to simulate the dynamic...