Did the Quaternary climatic fluctuations really influence the tempo and mode of diversification in European rodents?

The objective of this study was to establish whether the Quaternary climatic fluctuations influenced the tempo and mode of diversification in European rodents. Our case study is the subgenus Microtus (Terricola) distributed from western Europe to the Caucasus. Mitochondrial cytochrome b gene sequences from several representatives of all the species were used to generate maximum‐likelihood and Bayesian phylogenetic trees, to estimate divergence times, to identify biogeographic ancestral areas and to study the rate of diversification. Results showed that phylogenetic tree topologies were similar to previous published studies but with a better resolution at some nodes. The origin of Microtus (Terricola) is dated back to approximately 4.05 Myr in the Early Pliocene, and molecular dating for most Terricola species corresponds to several glacial periods of the Pleistocene. Results of the biogeographic ancestral area reconstruction suggest that Microtus (Terricola) diversified from the Caucasus/Turkey/Iran area through western Europe. Several periods of diversity variation were highlighted as follows: two period of diversity increase, between 3 and 2 Myr, and after 1 Myr; two periods of diversity decrease, before 3 Myr, and between 2 and 1 Myr. The diversification rate of Microtus (Terricola) was 0.353 ± 0.004 event/Myr, a rate similar to that of the Muridae family. To conclude, although the Pleistocene glacial conditions had an impact on the speciation events, the Quaternary does not appear however as a period with an exceptional rate of diversification for European rodents.     

Histone H4K20 tri‐methylation at late‐firing origins ensures timely heterochromatin replication

Among other targets, the protein lysine methyltransferase PR‐Set7 induces histone H4 lysine 20 monomethylation (H4K20me1), which is the substrate for further methylation by the Suv4‐20h methyltransferase. Although these enzymes have been implicated in control of replication origins, the specific contribution of H4K20 methylation to DNA replication remains unclear. Here, we show that H4K20 mutation in mammalian cells, unlike in Drosophila, partially impairs S‐phase progression and protects from DNA re‐replication induced by stabilization of PR‐Set7. Using Epstein–Barr virus‐derived episomes, we further demonstrate that conversion of H4K20me1 to higher H4K20me2/3 states by Suv4‐20h is not sufficient to define an efficient origin per se, but rather serves as an enhancer for MCM2‐7 helicase loading and replication activation at defined origins. Consistent with this, we find that Suv4‐20h‐mediated H4K20 tri‐methylation (H4K20me3) is required to sustain the licensing and activity of a subset of ORCA/LRWD1‐associated origins, which ensure proper replication timing of late‐replicating heterochromatin domains. Altogether, these results reveal Suv4‐20h‐mediated H4K20 tri‐methylation as a critical determinant in the selection of active replication initiation sites in heterochromatin regions of mammalian genomes.     

Enhanced detection of CNS cell secretome in plasma protein-depleted cerebrospinal fluid

Human cerebrospinal fluid (CSF) proteome is actively investigated to identify relevant biomarkers and therapeutic targets for neurological disorders. Approximately 80% of CSF proteome originate from plasma, yielding a high dynamic range in CSF protein concentration and precluding identification of potential biomarkers originating from CNS cells. Here, we have adapted the most complete multiaffinity depletion method available to remove 20 abundant plasma proteins from a CSF pool originating from patients with various cognitive disorders. We identified 622 unique CSF proteins in immunodepleted plus retained fractions versus 299 in native CSF, including 22 proteins hitherto not identified in CSF. Parallel analysis of neuronal secretome identified 34 major proteins secreted by cultured cortical neurons (cell adhesion molecules, proteins involved in neurite outgrowth and axonal guidance, modulators of synaptic transmission, proteases and protease inhibitors) of which 76% were detected with a high confidence in immunodepleted CSF versus 50% in native CSF. Moreover, a majority of proteins previously identified as secretory products of choroid plexus cells or astrocytes were detected in immunodepleted CSF. Hence, removal of 20 major plasma proteins from CSF improves detection of brain cell-derived proteins in CSF and should facilitate identification of relevant biomarkers in CSF proteome profiling analyses.     

Targeting telomeres to enforce cancer cells to senesce

The telomeres protect the end of chromosomes from being recognized and processed as an accidental double stranded break. In human somatic cells, telomeres shorten progressively with every round of DNA replication, leading to dysfunctional telomeres that trigger cellular senescence or apoptosis depending on the cell type. This telomere erosion appears to play a role in cell renewal, ageing and cancer. Two recent studies demonstrated in mouse that eroded telomeres in cancer cells blocked for apoptosis limit cancer formation by triggering senescence. These results suggest that provoking senescence may provide a way to cure cancer and point to new therapeutical strategies targeting specific telomeric functions. Nevertheless, an important question remains unanswered: does replicative senescence limit tumor formation in human?     

Carbonyl scavenger and antiatherogenic effects of hydrazine derivatives

Reactive carbonyl compounds (RCC) generated by polyunsaturated fatty acid oxidation alter progressively cellular and tissular proteins by forming adducts on free amino groups and thiol residues (carbonyl stress). Carbonyl scavengers may neutralize RCC, but their protective effect in atherosclerosis has not been extensively studied. We report the carbonyl scavenger and antiatherogenic properties of hydrazine derivatives, namely hydralazine, an antihypertensive drug, isoniazid, an antituberculosis agent, and two antidepressants, phenelzine and iproniazid. These drugs were poorly efficient in preventing the oxidation of LDL mediated by smooth muscle cells (SMCs), but inhibited the toxicity of UV-oxidized LDL (oxLDL) and of 4-hydroxynonenal (4-HNE). Hydrazine derivatives prevented the formation of foam cells resulting from LDL oxidation in human macrophagic U937 cells, and blocked the carbonyl stress in SMCs, by inhibiting the decrease in free amino group content, the increase in carbonylated proteins, and the formation of 4-HNE adducts on PDGFR. Experimental studies carried out on apoE-/- mice supplemented with drugs (30 mg/L in drinking water) showed a significant carbonyl stress inhibition correlated with a net reduction of atherosclerotic lesion development. In conclusion, these data indicate that hydrazine derivatives exhibit carbonyl scavenger and antiatherogenic properties, which opens novel therapeutical approaches for atherosclerosis and its cardiovascular complications.     

Sinorhizobium meliloti regulator MucR couples exopolysaccharide synthesis and motility

In order to enter symbiosis with its legume partner, Sinorhizobium meliloti requires regulatory systems for the appropriate responses to its environment. For example, motility is required for the chemotactic movement of bacteria toward the compounds released by its host, and exopolysaccharides (EPS) are required for bacterial attachment to the root or for invasion of the infection thread. Previous research has shown that ExoR/ExoS/ChvI as well as the ExpR/Sin quorum-sensing system inversely regulate both motility and EPS production, although the regulation mechanisms were unknown. We were able to attribute the ExpR-mediated regulation of motility to the ability of ExpR to bind a DNA sequence upstream of visN when activated by N-acyl-homoserine lactone. Furthermore, MucR, previously characterized as a regulator of EPS production, also affected motility. MucR inhibited expression of rem encoding an activator of motility gene expression and, consequently, the expression of Rem-regulated genes such as flaF and flgG. Binding of MucR to the rem promoter region was demonstrated and a sequence motif similar to the previously identified MucR binding consensus was identified within this region. The swarming ability of S. meliloti Rm2011 was shown to depend on a functional ExpR/Sin quorum-sensing system and the production of both flagella and EPS. Finally, we propose a model for the coordination of motility and EPS synthesis in S. meliloti.