Synthesis of 3'-deoxy-3'-C-methyl nucleoside derivatives

2',3'-Dideoxy-3'-C-methyl nucleosides bearing the five naturally occurring nucleic acid bases were synthesized. Additionally, the 3'-deoxy-3'-C-methyl nucleoside analogues bearing 5-aminoimidazole-4-carboxamide as well as 1,2,4-triazole-3-carboxamide moieties were prepared. The synthesis of the corresponding 2',3'-dideoxy-3'-C-methyl triazole derivative was also accomplished. The dideoxynucleoside derivatives were prepared by radical deoxygenation from their 3'-deoxy-3'-C-methyl parent ribonucleosides. When evaluated for their antiviral activity in cell culture experiments, none of these compounds showed any significant antiviral activity.     

Climate shaped the worldwide distribution of human mitochondrial DNA sequence variation

There is an ongoing discussion in the literature on whether human mitochondrial DNA (mtDNA) evolves neutrally. There have been previous claims for natural selection on human mtDNA based on an excess of non-synonymous mutations and higher evolutionary persistence of specific mitochondrial mutations in Arctic populations. However, these findings were not supported by the reanalysis of larger datasets. Using a geographical framework, we perform the first direct test of the relative extent to which climate and past demography have shaped the current spatial distribution of mtDNA sequences worldwide. We show that populations living in colder environments have lower mitochondrial diversity and that the genetic differentiation between pairs of populations correlates with difference in temperature. These associations were unique to mtDNA; we could not find a similar pattern in any other genetic marker. We were able to identify two correlated non-synonymous point mutations in the ND3 and ATP6 genes characterized by a clear association with temperature, which appear to be plausible targets of natural selection producing the association with climate. The same mutations have been previously shown to be associated with variation in mitochondrial pH and calcium dynamics. Our results indicate that natural selection mediated by climate has contributed to shape the current distribution of mtDNA sequences in humans.     

Lipase-catalyzed chemoselective aminolysis of various aminoalcohols with fatty acids

Candida antarctica lipase is well known to convert amines and alcohols into amides and esters. This report describes the development of a solvent-free enzymatic process for the production of fatty alkanolamides. The aminolysis of linoleyl ethyl ester with several aminoalcohols from C2 to C6 (linear or branched compounds), and the very high selectivity of amide compounds have been observed.Our investigation leads us to develop an original biotechnological process for the chemoselective synthesis of new active molecules for cutaneous application.     

Evolution of obesity by social status in France, 1981-2003

Although France is less affected by the rise in obesity than neighboring countries, the prevalence of obesity has increased, changing the distribution of this pathology in the population. We analyze this evolution by social status, education, income and gender, region of residence, using the three French national Health Surveys conducted in 1981, 1992 and 2003. The average body weight of both women and men has increased in France since 1981 and accelerated since the 1990s. This trend is obtained among all age groups. Nevertheless, this process did not affect all socioeconomic groups similarly. Geographical differences increased between north-east, where the prevalence of obesity is higher, and the Mediterranean region, where it is lower. Likewise, the gap between social and occupational categories has greatly widened: obesity has increased much faster among farmers and blue-collar workers than among managers and professionals. In contrast to women, poorer men are not more likely to be more obese than others. Our findings suggest that differences in BMI values increased substantially among social groups in France, in particular among women.     

Le trouble déficit de l’attention-hyperactivité et ses relations avec les conduites addictives

Attention deficit hyperactivity disorder (ADHD) is a common psychiatric comorbidity in substance use disorders. The aim of this article is to review the link between ADHD and addictive disorders. For this purpose, we will describe the clinical symptomatology of ADHD in adults and the prevalence of addiction in this population. We will broach the explanatory models for this comorbidity. Finally, we will evoke the long-term consequences of psychostimulant treatment in children with ADHD and the current treatment recommendations for substance users suffering from ADHD.     

Synthesis and preliminary evaluation of new 1- and 3-[1-(2-hydroxy-3-phenoxypropyl)]xanthines from 2-amino-2-oxazolines as potential A1 and A2A adenosine receptor antagonists

The development of potent and selective adenosine receptor ligands as potential drugs is an active area of research. Xanthines are one of the most important classes of adenosine receptor antagonists and have been widely developed in terms of affinity and selectivity for adenosine receptors. We recently developed new original pathways for the synthesis of xanthine analogues starting from 5-substituted-2-amino-2-oxazoline 5 as a synthon. These procedures allowed us to selectively introduce a large, functionalized and beta-adrenergic 2-hydroxy-3-phenoxypropyl pharmacophore at the 1- and 3-position of the xanthine moiety which allowed further structural modifications. In this study, we present a new synthetic access to racemic xanthine derivatives 1-4 from 5, and their evaluation as adenosine A1, A2A and A3 receptor ligands in radioligand binding studies. The 2-hydroxy-3-phenoxypropyl moiety was well tolerated in the 3-position of the xanthine core, while its introduction in the 1-position of the xanthine moiety led to a large decrease in adenosine receptor affinity. 1,7-Dimethyl-3-[1-(2-chloro-3-phenoxypropyl)]-8-(3,4,5-trimethoxystyryl)xanthine (2n) was the most potent and selective A2A antagonist of the present series (Ki=44 nM, >200-fold selective vs A1). 1-Propyl-3-[1-(2-hydroxy-3-phenoxypropyl)]-8-noradamantylxanthine (3f) was identified as a potent (KiA1=21 nM) and highly selective (>350-fold vs A2A and A3 receptor) adenosine A1 receptor antagonist.     

Reproductive constraints,not environmental conditions,shape the ontogeny of sex‐specific mass–size allometry in roe deer

In polygynous mammals, sex‐specific patterns of body growth are linked to divergent selection pressures on male and female body size, resulting in sexual dimorphism (SD). For males, reproductive success is generally linked to body size, hence, males should prioritise early growth. For females, reproductive success is linked to resource availability, so they may adopt a more conservative growth tactic. Using longitudinal monitoring of known‐age animals in two contrasting populations and an allometric approach to disentangle the relative contribution of structural size and physiological condition to SD, we addressed these issues in the weakly polygynous roe deer. Despite very different environmental conditions, we found remarkably similar patterns in the two populations in the mass–size allometric relationship at each life history stage, suggesting that relative allocation to structural size and physiological condition is highly constrained. SD in structural size (indexed by hind foot length) involved sex‐specific growth trajectories governed by a single mass–size allometric relationship during the juvenile stage, such that males were both bigger and heavier than females. In contrast, SD in physiological condition (indexed by the allometric relationship between body mass and hind foot length, expressed as body mass for a given body size) developed markedly during the sub‐adult stage in relation to sex differences in the timing of first reproduction. Among adults, males were heavier for a given size than females, suggesting that, relative to females, males express a capital breeder tactic, accumulating fat reserves to offset reproductive costs. By the senescent stage, SD in physiological condition had disappeared, with both sexes governed by a single allometric relationship, suggesting more rapid senescence in males than females. Individuals born into poor cohorts were generally lighter for a given size, indicating growth priority for skeletal size over physiological condition in both sexes. However, sex differences in cohort effects among sub‐adults resulted in lower size‐specific SD in poor cohorts, indicating that body condition of sub‐adult females is buffered against environmental harshness. We conclude that sex‐differences in reproductive tactics impose constraints on the ontogeny of SD in roe deer, leading to sex‐specific trajectories in structural size and physiological condition.     

Protective cross talk between activated protein C and TNF signaling in vascular endothelial cells: implication of EPCR, noncanonical NF-κB, and ERK1/2 MAP kinases

Activated protein C (APC) is a natural anticoagulant protease that displays cytoprotective and antiinflammatory activities and has been demonstrated to reduce mortality of patients with severe sepsis. However, APC signaling is not fully understood. This study further investigated the antiinflammatory effects of APC in vascular endothelial cells (EC) and examined the cross talk between APC and TNF signaling. Analysis of the regulatory mechanisms mediated by APC on vascular human EC shows that APC impairs TNF signaling by triggering a preemptive activation of intracellular pathways. We found that APC signaling causes a moderate but significant induction of cell adhesion molecules (CAMs) including VCAM-1 at mRNA and protein levels. Activation of the noncanonical NF-κB and ERK1/2 are both pivotal to APC signaling leading to VCAM-1 expression. APC upregulates TNF receptor-associated factor 2 (TRAF2) and phosphorylates NF-κB p65 at Ser276 and Ser536 independently of IκB degradation. The ultimate protective antiinflammatory effect of APC in response to TNF is associated with a sustained activation of ERK1/2 and Akt while phosphorylation of NF-κB p65 is precluded. Inhibitors of ERK (PD98059 and U0126) abolish the antiinflammatory signal mediated by APC. Blocking antibodies and silencing assays also suggest that, in EC, protease-activated receptor 1 and endothelial protein C receptor (EPCR) both conduct ERK activation and VCAM-1 induction in response to APC. To conclude, APC protects EC by attenuating CAM expression during inflammation. APC engages a regulatory cross talk involving EPCR, ERK, and NF-κB that impairs TNF signaling.     

Immune evasion by Helicobacter pylori is mediated by induction of macrophage arginase II

Helicobacter pylori infection persists for the life of the host due to the failure of the immune response to eradicate the bacterium. Determining how H. pylori escapes the immune response in its gastric niche is clinically important. We have demonstrated in vitro that macrophage NO production can kill H. pylori, but induction of macrophage arginase II (Arg2) inhibits inducible NO synthase (iNOS) translation, causes apoptosis, and restricts bacterial killing. Using a chronic H. pylori infection model, we determined whether Arg2 impairs host defense in vivo. In C57BL/6 mice, expression of Arg2, but not arginase I, was abundant and localized to gastric macrophages. Arg2(-/-) mice had increased histologic gastritis and decreased bacterial colonization compared with wild-type (WT) mice. Increased gastritis scores correlated with decreased colonization in individual Arg2(-/-) mice but not in WT mice. When mice infected with H. pylori were compared, Arg2(-/-) mice had more gastric macrophages, more of these cells were iNOS(+), and these cells expressed higher levels of iNOS protein, as determined by flow cytometry and immunofluorescence microscopy. There was enhanced nitrotyrosine staining in infected Arg2(-/-) versus WT mice, indicating increased NO generation. Infected Arg2(-/-) mice exhibited decreased macrophage apoptosis, as well as enhanced IFN-γ, IL-17a, and IL-12p40 expression, and reduced IL-10 levels consistent with a more vigorous Th1/Th17 response. These studies demonstrate that Arg2 contributes to the immune evasion of H. pylori by limiting macrophage iNOS protein expression and NO production, mediating macrophage apoptosis, and restraining proinflammatory cytokine responses.     

Prion permissive pathways: extracellular matrix genes control susceptibility to prion infection

There are wide variations in the susceptibility of humans, animals, and cultured cell lines to infection by prions. In this issue of The EMBO Journal, Marbiah et al ( 2014 ) identified a gene regulatory network that regulates the susceptibility of cultured cells to prion infection. Surprisingly, a number of these genes impact the structure of the extracellular matrix. These results have important implications for understanding mechanisms of prion infection and also suggest new therapeutic targets.