Synthesis of novel 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues and evaluation of their inhibitory activity against Ser/Thr kinases

The efficient synthesis of 7-substituted pyrido[2′,3′:4,5]furo[3,2-d]pyrimidin-4-amines and their N-aryl analogues is described. 3,5-Dibromopyridine was converted into 3-amino-6-bromofuro[3,2-b]pyridine-2-carbonitrile intermediate which was formylated with DMFDMA. Functionalization at position 7 of the tricyclic scaffold was accomplished, before or after cyclisation step, by palladium-catalyzed Suzuki–Miyaura cross-coupling while the pyrimidin-4-amines and N-aryl counterparts were synthesized by microwave-assisted formamide degradation and Dimroth rearrangement, respectively. The final products were evaluated for their potent inhibition of a series of five Ser/Thr kinases (CDK5/p25, CK1δ/ε, CLK1, DYRK1A, GSK3α/β). Compound 35 showed the best inhibitory activity with an IC₅₀ value of 49 nM and proved to be specific to CLK1 among the panel of tested kinases.     

Flaxseed (Linum usitatissimum L.) extract as well as (+)-secoisolariciresinol diglucoside and its mammalian derivatives are potent inhibitors of α-amylase activity

Type 2 diabetes mellitus (T2DM) is one of the common global diseases. Flaxseed is by far the richest source of the dietary lignans (i.e., secoisolariciresinol diglucoside) which have been shown to delay the development of T2DM in animal models. Herein, we propose the first evidences for a mechanism of action involving the inhibition of the pancreatic α-amylase (EC 3.2.1.1) by flaxseed-derived lignans that could therefore constitute a promising nutraceutical for the prevention and the treatment of T2DM.     

Is the continental life of the European eel Anguilla anguilla affected by the parasitic invader Anguillicoloides crassus?

Quantifying the fitness cost that parasites impose on wild hosts is a challenging task, because the epidemiological history of field-sampled hosts is often unknown. In this study, we used an internal marker of the parasite pressure on individual hosts to evaluate the costs of parasitism with respect to host body condition, size increase and reproductive potential of field-collected animals for which we also determined individual age. In our investigated system, the European eel Anguilla anguilla and the parasitic invader Anguillicoloides crassus, high virulence and severe impacts are expected because the host lacks an adaptive immune response. We demonstrated a nonlinear relationship between the severity of damage to the affected organ (i.e. the swimbladder, our internal marker) and parasite abundance and biomass, thus showing that the use of classical epidemiological parameters was not relevant here. Surprisingly, we found that the most severely affected eels (with damaged swimbladder) had greater body length and mass (+11% and +41%, respectively), than unaffected eels of same age. We discuss mechanisms that could explain this finding and other counterintuitive results in this host–parasite system, and highlight the likely importance of host panmixia in generating great inter-individual variability in growth potential and infection risk. Under that scenario, the most active foragers would not only have the greatest size increase, but also the highest probability of becoming repeatedly infected—via trophic parasite transmission—during their continental life.     

A Systematic Approach for the Genetic Dissection of Protein Complexes in Living Cells

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Single‐nucleotide polymorphism discovery and diversity in the model legume Medicago truncatula

Extensive genomic resources are available in the model legume Medicago truncatula. Here, we present the discovery and design of the first array of single‐nucleotide polymorphism (SNP) markers in M. truncatula through large‐scale Sanger resequencing of genomic fragments spanning the genome, in a diverse panel of 16 M. truncatula accessions. Both anonymous fragments and fragments targeting candidate genes for flowering phenology and symbiosis were surveyed for nucleotide variation in almost 230 kb of unique genomic regions. A set of 384 SNP markers was designed for an Illumina's GoldenGate assay, genotyped on a collection of 192 inbred lines (CC192) representing the geographical range of the species and used to survey the diversity of two natural populations. Finally, 86% of the tested SNPs were of high quality and exhibited polymorphism in the CC192 collection. Even at the population level, we detected polymorphism for more than 50% of the selected SNPs. Analysis of the allele frequency spectrum in the CC192 showed a reduced ascertainment bias, mostly limited to very rare alleles (frequency <0.01). The substantial polymorphism detected at the species and population levels, the high marker quality and the potential to survey large samples of individuals make this set of SNP markers a valuable tool to improve our understanding of the effect of demographic and selective factors that shape the natural genetic diversity within the selfing species Medicago truncatula.     

Blood Microbiota Dysbiosis Is Associated with the Onset of Cardiovascular Events in a Large General Population: The D.E.S.I.R. Study

Aim

We recently described a human blood microbiome and a connection between this microbiome and the onset of diabetes. The aim of the current study was to assess the association between blood microbiota and incident cardiovascular disease.

Methods and Results

D.E.S.I.R. is a longitudinal study with the primary aim of describing the natural history of the metabolic syndrome and its complications. Participants were evaluated at inclusion and at 3-, 6-, and 9-yearly follow-up visits. The 16S ribosomal DNA bacterial gene sequence, that is common to the vast majority of bacteria (Eubac) and a sequence that mostly represents Proteobacteria (Pbac), were measured in blood collected at baseline from 3936 participants. 73 incident cases of acute cardiovascular events, including 30 myocardial infarctions were recorded. Eubac was positively correlated with Pbac (r = 0.59; P<0.0001). In those destined to have cardiovascular complications, Eubac was lower (0.14±0.26 vs 0.12±0.29 ng/µl; P = 0.02) whereas a non significant increase in Pbac was observed. In multivariate Cox analysis, Eubac was inversely correlated with the onset of cardiovascular complications, (hazards ratio 0.50 95% CI 0.35–0.70) whereas Pbac (1.56, 95%CI 1.12–2.15) was directly correlated.

Conclusion

Pbac and Eubac were shown to be independent markers of the risk of cardiovascular disease. This finding is evidence for the new concept of the role played by blood microbiota dysbiosis on atherothrombotic disease. This concept may help to elucidate the relation between bacteria and cardiovascular disease.     

Does Recall after Sleep-Dependent Memory Consolidation Reinstate Sensitivity to Retroactive Interference?

Previous studies have shown that newly encoded memories are more resistant to retroactive interference when participants are allowed to sleep after learning the original material, suggesting a sleep-related strengthening of memories. In the present study, we investigated delayed, long-term effects of sleep vs. sleep deprivation (SD) on the first post-training night on memory consolidation and resistance to interference. On day 1, participants learned a list of unrelated word pairs (AB), either in the morning or in the evening, then spent the post-training night in a sleep or sleep deprivation condition, in a within-subject paradigm. On day 4, at the same time of day, they learned a novel list of word pairs (AC) in which 50% of the word pairs stemmed with the same word than in the AB list, resulting in retroactive interference. Participants had then to recall items from the AB list upon presentation of the “A” stem. Recall was marginally improved in the evening, as compared to the morning learning group. Most importantly, retroactive interference effects were found in the sleep evening group only, contrary to the hypothesis that sleep exerts a protective role against intrusion by novel but similar learning. We tentatively suggest that these results can be explained in the framework of the memory reconsolidation theory, stating that exposure to similar information sets back consolidated items in a labile form again sensitive to retroactive interference. In this context, sleep might not protect against interference but would promote an update of existing episodic memories while preventing saturation of the memory network due to the accumulation of dual traces.     

Formal Models of the Network Co-occurrence Underlying Mental Operations

Systems neuroscience has identified a set of canonical large-scale networks in humans. These have predominantly been characterized by resting-state analyses of the task-unconstrained, mind-wandering brain. Their explicit relationship to defined task performance is largely unknown and remains challenging. The present work contributes a multivariate statistical learning approach that can extract the major brain networks and quantify their configuration during various psychological tasks. The method is validated in two extensive datasets (n = 500 and n = 81) by model-based generation of synthetic activity maps from recombination of shared network topographies. To study a use case, we formally revisited the poorly understood difference between neural activity underlying idling versus goal-directed behavior. We demonstrate that task-specific neural activity patterns can be explained by plausible combinations of resting-state networks. The possibility of decomposing a mental task into the relative contributions of major brain networks, the "network co-occurrence architecture" of a given task, opens an alternative access to the neural substrates of human cognition.