Novel triazolopyridylbenzamides as potent and selective p38α inhibitors

A new class of p38α inhibitors based on a biaryl-triazolopyridine scaffold was investigated. X-ray crystallographic data of the initial lead compound cocrystallised with p38α was crucial in order to uncover a unique binding mode of the inhibitor to the hinge region via a pair of water molecules. Synthesis and SAR was directed towards the improvement of binding affinity, as well as ADME properties for this new class of p38α inhibitors and ultimately afforded compounds showing good in vivo efficacy.     

The fanconi anemia pathway limits human papillomavirus replication

High-risk human papillomaviruses (HPVs) deregulate epidermal differentiation and cause anogenital and head and neck squamous cell carcinomas (SCCs). The E7 gene is considered the predominant viral oncogene and drives proliferation and genome instability. While the implementation of routine screens has greatly reduced the incidence of cervical cancers which are almost exclusively HPV positive, the proportion of HPV-positive head and neck SCCs is on the rise. High levels of HPV oncogene expression and genome load are linked to disease progression, but genetic risk factors that regulate oncogene abundance and/or genome amplification remain poorly understood. Fanconi anemia (FA) is a genome instability syndrome characterized at least in part by extreme susceptibility to SCCs. FA results from mutations in one of 15 genes in the FA pathway, whose protein products assemble in the nucleus and play important roles in DNA damage repair. We report here that loss of FA pathway components FANCA and FANCD2 stimulates E7 protein accumulation in human keratinocytes and causes increased epithelial proliferation and basal cell layer expansion in the HPV-positive epidermis. Additionally, FANCD2 loss stimulates HPV genome amplification in differentiating cells, demonstrating that the intact FA pathway functions to restrict the HPV life cycle. These findings raise the possibility that FA genes suppress HPV infection and disease and suggest possible mechanism(s) for reported associations of HPV with an FA cohort in Brazil and for allelic variation of FA genes with HPV persistence in the general population.     

Mafb and c-Maf Have Prenatal Compensatory and Postnatal Antagonistic Roles in Cortical Interneuron Fate and Function

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Lysosomal Signaling Licenses Embryonic Stem Cell Differentiation via Inactivation of Tfe3

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Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria

A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84?nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies.     

Diversity-stability relationships in community ecology: re-examination of the portfolio effect

In plant communities, the portfolio effect, also called "statistical averaging effect", expresses the fact that stability in aggregate community properties such as biomass productivity generally rises with species diversity, simply because of the statistical averaging of the fluctuations in species' properties. This paper essentially upgrades the previous formulations of the portfolio effect, first developed by Doak and collaborators and then by Tilman. It uses a theoretical approach based on simple statistical relationships and some simplifying assumptions proposed by these authors. The new formulation presented extends and improves the previous relationships in the sense that it takes into account simultaneously a varying scaling power of the variance, the interaction effect between species, the heterogeneity in species productivity and interspecies correlated responses to the environment. It appears that the simple statistical averaging, as inferred from this formulation, does not necessarily lead to a positive correlation between species diversity and community stability.     

cGMP-mediated signaling via cGKIalpha is required for the guidance and connectivity of sensory axons

Previous in vitro studies using cGMP or cAMP revealed a cross-talk between signaling mechanisms activated by axonal guidance receptors. However, the molecular elements modulated by cyclic nucleotides in growth cones are not well understood. cGMP is a second messenger with several distinct targets including cGMP-dependent protein kinase I (cGKI). Our studies indicated that the alpha isoform of cGKI is predominantly expressed by sensory axons during developmental stages, whereas most spinal cord neurons are negative for cGKI. Analysis of the trajectories of axons within the spinal cord showed a longitudinal guidance defect of sensory axons within the developing dorsal root entry zone in the absence of cGKI. Consequently, in cGKI-deficient mice, fewer axons grow within the dorsal funiculus of the spinal cord, and lamina-specific innervation, especially by nociceptive sensory neurons, is strongly reduced as deduced from anti-trkA staining. These axon guidance defects in cGKI-deficient mice lead to a substantial impairment in nociceptive flexion reflexes, shown using electrophysiology. In vitro studies revealed that activation of cGKI in embryonic dorsal root ganglia counteracts semaphorin 3A-induced growth cone collapse. Our studies therefore reveal that cGMP signaling is important for axonal growth in vivo and in vitro.     

Pup Shoving by Adult Naked Mole-Rats

Adult naked mole‐rats (Heterocephalus glaber) characteristically perform an unusual behavior toward young: they shove small pups frequently and vigorously around the nest. We studied 15 litters in five captive colonies to quantify which adults shove pups, changes in shoving frequencies as pups develop, how external disturbances affect pup‐shoving frequencies, and behavior of juveniles that were not shoved as pups. In all litters and colonies the breeding female shoved pups significantly more often than any other individual. Breeding females also shoved adult colony mates, but at far lower rates than they shoved pups. Breeding males shoved pups about half as often as did breeding females. Together, the parents shoved pups ten times more often than did nonbreeders. Frequencies of pup shoving peaked when pups were 3–4 wk old, roughly coincident with weaning. When colonies were disturbed experimentally, frequencies of pup shoving increased dramatically, whereas rates at which nonbreeding adults were shoved decreased sharply. We separated four newly‐weaned litters and raised half the pups apart from their colony. When these litters were reunited 4–9 wk later, the unshoved (experimental) pups were the same size as the frequently shoved (control) pups, but the unshoved pups were significantly less likely to flee from a disturbance. Shoving of small pups encourages them to flee from danger, and also may enforce weaning.     

Redefining Phrymaceae: the placement of Mimulus, tribe Mimuleae, and Phryma

Chloroplast trnL/F and nuclear ribosomal ITS and ETS sequence data were used to analyze phylogenetic relationships among members of tribe Mimuleae (Scrophulariaceae) and other closely related families in Lamiales. The results of these analyses led to the following conclusions. (1) The Australian genera Glossostigma and Peplidium and the taxonomically isolated Phryma join four genera of tribe Mimuleae to form a well-supported clade that is distinct from other families in the Lamiales. We refer to that clade as the subfamily Phrymoideae. (2) The genera Mazus and Lancea (tribe Mimuleae) together form a well-supported clade that we recognize as the subfamily Mazoideae. Mazoideae is weakly supported as sister to Phrymoideae. We assign Mazoideae and Phrymoideae to a redefined family Phrymaceae. (3) Mimulus is not monophyletic, because members of at least six other genera have been derived from within it. In light of the molecular evidence, it is clear that species of Phrymaceae (about 190 species) have undergone two geographically distinct radiations; one in western North America (about 130 species) and another in Australia (about 30 species). Phylogenetic interpretations of morphological evolution and biogeographical patterns are discussed.     

Culture-Independent Investigation of the Microbiome Associated with the Nematode Acrobeloides maximus

Background

Symbioses between metazoans and microbes are widespread and vital to many ecosystems. Recent work with several nematode species has suggested that strong associations with microbial symbionts may also be common among members of this phylu. In this work we explore possible symbiosis between bacteria and the free living soil bacteriovorous nematode Acrobeloides maximus.

Methodology

We used a soil microcosm approach to expose A. maximus populations grown monoxenically on RFP labeled Escherichia coli in a soil slurry. Worms were recovered by density gradient separation and examined using both culture-independent and isolation methods. A 16S rRNA gene survey of the worm-associated bacteria was compared to the soil and to a similar analysis using Caenorhabditis elegans N2. Recovered A. maximus populations were maintained on cholesterol agar and sampled to examine the population dynamics of the microbiome.

Results

A consistent core microbiome was extracted from A. maximus that differed from those in the bulk soil or the C. elegans associated set. Three genera, Ochrobactrum, Pedobacter, and Chitinophaga, were identified at high levels only in the A. maximus populations, which were less diverse than the assemblage associated with C. elegans. Putative symbiont populations were maintained for at least 4 months post inoculation, although the levels decreased as the culture aged. Fluorescence in situ hybridization (FISH) using probes specific for Ochrobactrum and Pedobacter stained bacterial cells in formaldehyde fixed nematode guts.

Conclusions

Three microorganisms were repeatedly observed in association with Acrobeloides maximus when recovered from soil microcosms. We isolated several Ochrobactrum sp. and Pedobacter sp., and demonstrated that they inhabit the nematode gut by FISH. Although their role in A. maximus is not resolved, we propose possible mutualistic roles for these bacteria in protection of the host against pathogens and facilitating enzymatic digestion of other ingested bacteria.