BAGE genes generated by juxtacentromeric reshuffling in the Hominidae lineage are under selective pressure

In this paper, we show that the BAGE (B melanoma antigen) gene family was generated by chromosome rearrangements that occurred during the evolution of hominoids. An 84-kb DNA fragment derived from the phylogenetic 7q36 region was duplicated in the juxtacentromeric region of either chromosome 13 or chromosome 21. The duplicated region contained a fragment of the MLL3 gene, which, after juxtacentromeric reshuffling, generated the ancestral BAGE gene. Then, this ancestral gene gave rise to several independent genes through successive rounds of inter- and intrachromosome duplications. Comparison of synonymous and nonsynonymous mutations in putative coding regions shows that BAGE genes, but not the BAGE gene fragments, are under selective pressure. Our data strongly suggest that BAGE proteins have a function and that juxtacentromeric regions, whose plasticity is now largely proved, are not a simple junkyard of gene fragments, but may be the birth site of novel genes.     

Are 5'-O-carbamate-2',3'-dideoxythiacytidine new anti-HIV and anti-HBV nucleoside drugs or prodrugs?

In contrast to 5'-O-carbonate 3TC derivatives (23, 24), which are clearly 3TC prodrugs, the corresponding 3TC carbamates (15-21 and 25), found to be very stable compounds with respect to enzymatic hydrolysis (cellular lysates and culture cell media) and still active on both HIV-1 and HBV infected cells, may not be 3TC prodrugs. The antiviral properties as well as the mechanism of action of 3TC analogues have been studied and evaluated.     

MicroRNA-146a suppresses metastatic activity in brain metastasis

Primary lung tumors, breast tumors, and melanoma metastasize mainly in the brain where therapy is limited to surgery and radiation. To investigate the molecular basis of brain metastases, we isolated brain-trophic metastatic MDA-MB-435-LvBr2 (LvBr2) cells via left ventricle (LV) injection of MDA-MB-435 cells into immunodeficiency (NOD/SCID) mice. Whereas parent MDA-MB-435 cells displayed an elongated morphology, LvBr2 cells were round and displayed an aggregated distribution. LvBr2 cells expressed lower β-catenin levels and higher heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNPC) levels than parental cells. Since microRNAs are known to play an important role in cancer progression including metastasis, we screened microRNAs expressed specifically in brain metastases. MicroRNA-146a was almost undetectable in LvBr2 cells and highly expressed in the parental cells. Overexpression of miR-146a increased β-catenin expression and suppressed the migratory and invasive activity of LvBr2 cells. The miR-146a-elicited decrease in hnRNPC in turn lowered the expression of MMP-1, uPA, and uPAR and inhibited the migratory and invasive activity of LvBr2 cells. Taken together, our findings indicate that miR-146a is virtually absent from brain metastases and can suppress their metastatic potential including their migratory and invasive activities associated with upregulation of β-catenin and downregulation of hnRNPC.     

Effects of whole-body vibration training on explosive strength and postural control in young female athletes

This study aimed to evaluate the effectiveness of a whole-body vibration training program to improve neuromuscular performance in young elite female athletes. Twenty-three women basketball players (14-18 years old) were randomly assigned to a control group (CG, n = 11) or to a whole-body vibration group (WBVG, n = 12). During the study period, both groups continued their usual training program, but the WBVG also underwent a 15-week vibration training program. We analyzed the countermovement jump test (CMJ), the 1-leg hop test for the right leg and for the left leg, and the single-limb standing balance for both legs and with eyes open and closed at 3 time points: before training (T1), after an 8-week training period (T2), and after a further 7-week training period (T3). Compared with the CG, CMJ increased significantly in the WBVG from T1 to T2 (6.47%, p < 0.001), T1 to T3 (10.07%, p = 0.005), and T2 to T3 (3.38%, p < 0.001). One-leg hop test for the right and left legs also showed significantly higher values in WBVG from T1 to T2 (10.12%, p < 0.001 and 9.63%, p = 0.002, respectively) and T1 to T3 (14.17%, p = 0.001 and 15.17%, p = 0.004, respectively). Lateral deviation of the center of pressure in the closed eyes test decreased significantly in WBVG for both right and left leg, from T1 to T2 (-22.20%, p = 0.043 and -34.77%, p < 0.001, respectively) and from T1 to T3 (-33.14%, p = 0.027 and -33.58%, p = 0.043, respectively) compared with the CG. In conclusion, our results show that a 15-week whole-body vibration training program improves explosive strength and postural stability in adolescent female basketball players.     

Effects of inbreeding and interpopulation crosses on performance and plasticity of two generations of offspring of a declining grassland plant

? Premise of the study: Inbreeding depression is a major evolutionary force and an important topic in conservation genetics because habitat fragmentation leads to increased inbreeding in the populations of many species. Crosses between populations may restore heterozygosity, resulting in increased performance (heterosis), but may also lead to the disruption of coadapted gene complexes and to decreased performance (outbreeding depression). ? Methods: We investigated the effects of selfing and of within and between population crosses on reproduction and the performance of two generations of offspring of the declining grassland plant Saxifraga granulata (Saxifragaceae). We also subjected the first generation of offspring to a fertilization and two stress treatments (competition and defoliation) to investigate whether the effects of inbreeding and interpopulation gene flow depend on environmental conditions. ? Key results: Inbreeding depression affected all traits in the F(1) generation (δ = 0.07-0.55), but was stronger for traits expressed late during development and varied among families. The adaptive plasticity of offspring from selfing and from interpopulation crosses in response to nutrient addition was reduced. Outbreeding depression was also observed in response to stress. Multiplicative fitness of the F(2) generation after serial inbreeding was extremely low (δ > 0.99), but there was heterosis after crossing inbred lines. Outbreeding depression was not observed in the F(2). ? Conclusions: Continuous inbreeding may drastically reduce the fitness of plants, but effects may be environment-dependent. When assessing the genetic effects of fragmentation and interpopulation crosses, the possible effects on the mean performance of offspring and on its adaptive plasticity should be considered.     

Cropping practices modulate the impact of glyphosate on arbuscular mycorrhizal fungi and rhizosphere bacteria in agroecosystems of the semiarid prairie

A growing body of evidence obtained from studies performed under controlled conditions suggests that glyphosate use can modify microbial community assemblages. However, few studies have examined the influence of glyphosate in agroecosystems. We examined 4 wheat-based production systems typical of the Canadian prairie over 2 years to answer the following question: Does preseeding of glyphosate impact soil rhizosphere microorganisms? If so, do cropping practices influence this impact? Glyphosate caused a shift in the species dominating the arbuscular mycorrhizal fungal community in the rhizosphere, possibly through the modification of host plant physiology. Glyphosate stimulated rhizobacterial growth while having no influence on saprotrophic fungi, suggesting a greater abundance of glyphosate-tolerant 5-enolpyruvylshikimate-3-phosphate synthase (EPSPS) in bacteria than in fungi. Glyphosate stimulated rhizosphere bacteria in pea but not in urea-fertilized durum wheat, which is consistent with inhibition of EPSPS tolerance to residual glyphosate through high ammonium levels. Mitigation of the effects of glyphosate on rhizosphere bacteria through tillage suggests a reduction in residual glyphosate activity through increased adsorption to soil binding sites upon soil mixing. The influence of glyphosate on Gram-negative bacteria was mitigated under drought conditions in 2007. Our experiment suggests that interactions between soil fertility, tillage, and cropping practices shape the influence of glyphosate use on rhizosphere microorganisms.     

Annexin A2 and A5 Serve as New Ligands for C1q on Apoptotic Cells

C1q is the initiator of the classical complement pathway and opsonizes apoptotic cells to facilitate phagocytosis. Deficiency of C1q is the strongest known risk factor for development of systemic lupus erythematosus (SLE), which appears to be related to ensuing impaired clearance of apoptotic material. The objective of the current study was to investigate new ligands for C1q on the surface of apoptotic cells. We revealed that the two phospholipid-binding proteins annexin A2 and A5 are, beside DNA, significant C1q ligands. We furthermore, demonstrated that C1q binds directly to histones exposed on the surface of dying cells but we did not detect significant interaction with phosphatidylserine. The complement inhibitors C4b-binding protein and factor H also interact with dying cells, most likely to decrease complement activation beyond the level of C3 to allow noninflammatory clearance. Despite the fact that C4b-binding protein, factor H, and C1q share some ligands on dying cells, we showed that these three proteins did not compete with one another for binding to apoptotic cells. We additionally demonstrated that the way in which apoptosis is induced influenced both the degree of apoptosis and the binding of C1q. The knowledge, that annexin A2 and A5 act as ligands for C1q on apoptotic cells, sheds new light on the pathophysiology of autoimmune diseases.     

A flavivirus protein M-derived peptide directly permeabilizes mitochondrial membranes, triggers cell death and reduces human tumor growth in nude mice

Dengue viruses belong to the Flavivirus family and are responsible for hemorrhagic fever in Human. Dengue virus infection triggers apoptosis especially through the expression of the small membrane (M) protein. Using isolated mitochondria, we found that synthetic peptides containing the C-terminus part of the M ectodomain caused apoptosis-related mitochondrial membrane permeabilization (MMP) events. These events include matrix swelling and the dissipation of the mitochondrial transmembrane potential (ΔΨ_m). Protein M Flavivirus sequence alignments and helical wheel projections reveal a conserved distribution of charged residues. Moreover, when combined to the cell penetrating HIV-1 Tat peptide transduction domain (Tat-PTD), this sequence triggers a caspase-dependent cell death associated with ΔΨ_m loss and cytochrome c release. Mutational approaches coupled to functional screening on isolated mitochondria resulted in the selection of a protein M derived sequence containing nine residues with potent MMP-inducing properties on isolated mitochondria. A chimeric peptide composed of a Tat-PTD linked to the 9-mer entity triggers MMP and cell death. Finally, local administration of this chimeric peptide induces growth inhibition of xenograft prostate PC3 tumors in immuno-compromised mice, and significantly enhances animal survival. Together, these findings support the notion of using viral genomes as valuable sources to discover mitochondria-targeted sequences that may lead to the development of new anticancer compounds.