Control of bone resorption in mice by Schnurri-3

Mice lacking the large zinc finger protein Schnurri-3 (Shn3) display increased bone mass, in part, attributable to augmented osteoblastic bone formation. Here, we show that in addition to regulating bone formation, Shn3 indirectly controls bone resorption by osteoclasts in vivo. Although Shn3 plays no cell-intrinsic role in osteoclasts, Shn3-deficient animals show decreased serum markers of bone turnover. Mesenchymal cells lacking Shn3 are defective in promoting osteoclastogenesis in response to selective stimuli, likely attributable to reduced expression of the key osteoclastogenic factor receptor activator of nuclear factor-κB ligand. The bone phenotype of Shn3-deficient mice becomes more pronounced with age, and mice lacking Shn3 are completely resistant to disuse osteopenia, a process that requires functional osteoclasts. Finally, selective deletion of Shn3 in the mesenchymal lineage recapitulates the high bone mass phenotype of global Shn3 KO mice, including reduced osteoclastic bone catabolism in vivo, indicating that Shn3 expression in mesenchymal cells directly controls osteoblastic bone formation and indirectly regulates osteoclastic bone resorption.     

SAMBA, a plant-specific anaphase-promoting complex/cyclosome regulator is involved in early development and A-type cyclin stabilization

The anaphase-promoting complex/cyclosome (APC/C) is a large multiprotein E3 ubiquitin ligase involved in ubiquitin-dependent proteolysis of key cell cycle regulatory proteins, including the destruction of mitotic cyclins at the metaphase-to-anaphase transition. Despite its importance, the role of the APC/C in plant cells and the regulation of its activity during cell division remain poorly understood. Here, we describe the identification of a plant-specific negative regulator of the APC/C complex, designated SAMBA. In Arabidopsis thaliana, SAMBA is expressed during embryogenesis and early plant development and plays a key role in organ size control. Samba mutants produced larger seeds, leaves, and roots, which resulted from enlarged root and shoot apical meristems, and, additionally, they had a reduced fertility attributable to a hampered male gametogenesis. Inactivation of SAMBA stabilized A2-type cyclins during early development. Our data suggest that SAMBA regulates cell proliferation during early development by targeting CYCLIN A2 for APC/C-mediated proteolysis.     

Unifying the spatial epidemiology and molecular evolution of emerging epidemics

We introduce a conceptual bridge between the previously unlinked fields of phylogenetics and mathematical spatial ecology, which enables the spatial parameters of an emerging epidemic to be directly estimated from sampled pathogen genome sequences. By using phylogenetic history to correct for spatial autocorrelation, we illustrate how a fundamental spatial variable, the diffusion coefficient, can be estimated using robust nonparametric statistics, and how heterogeneity in dispersal can be readily quantified. We apply this framework to the spread of the West Nile virus across North America, an important recent instance of spatial invasion by an emerging infectious disease. We demonstrate that the dispersal of West Nile virus is greater and far more variable than previously measured, such that its dissemination was critically determined by rare, long-range movements that are unlikely to be discerned during field observations. Our results indicate that, by ignoring this heterogeneity, previous models of the epidemic have substantially overestimated its basic reproductive number. More generally, our approach demonstrates that easily obtainable genetic data can be used to measure the spatial dynamics of natural populations that are otherwise difficult or costly to quantify.     

Bacteriophage T4 polynucleotide kinase triggers degradation of mRNAs

The bacteriophage T4-encoded RegB endoribonuclease is produced during the early stage of phage development and targets mostly (but not exclusively) the Shine-Dalgarno sequences of early genes. In this work, we show that the degradation of RegB-cleaved mRNAs depends on a functional T4 polynucleotide kinase/phosphatase (PNK). The 5'-OH produced by RegB cleavage is phosphorylated by the kinase activity of PNK. This modification allows host RNases G and E, with activity that is strongly stimulated by 5'-monophosphate termini, to attack mRNAs from the 5'-end, causing their destabilization. The PNK-dependent pathway of degradation becomes effective 5 min postinfection, consistent with our finding that several minutes are required for PNK to accumulate after infection. Our work emphasizes the importance of the nature of the 5' terminus for mRNA stability and depicts a pathway of mRNA degradation with 5'- to 3'-polarity in cells devoid of 5'-3' exonucleases. It also ascribes a role for T4 PNK during normal phage development.     

Evolutionary constraints on visual cortex architecture from the dynamics of hallucinations

In the cat or primate primary visual cortex (V1), normal vision corresponds to a state where neural excitation patterns are driven by external visual stimuli. A spectacular failure mode of V1 occurs when such patterns are overwhelmed by spontaneously generated spatially self-organized patterns of neural excitation. These are experienced as geometric visual hallucinations. The problem of identifying the mechanisms by which V1 avoids this failure is made acute by recent advances in the statistical mechanics of pattern formation, which suggest that the hallucinatory state should be very robust. Here, we report how incorporating physiologically realistic long-range connections between inhibitory neurons changes the behavior of a model of V1. We find that the sparsity of long-range inhibition in V1 plays a previously unrecognized but key functional role in preserving the normal vision state. Surprisingly, it also contributes to the observed regularity of geometric visual hallucinations. Our results provide an explanation for the observed sparsity of long-range inhibition in V1--this generic architectural feature is an evolutionary adaptation that tunes V1 to the normal vision state. In addition, it has been shown that exactly the same long-range connections play a key role in the development of orientation preference maps. Thus V1's most striking long-range features--patchy excitatory connections and sparse inhibitory connections--are strongly constrained by two requirements: the need for the visual state to be robust and the developmental requirements of the orientational preference map.     

Strong relationship between elemental stoichiometry and metabolome in plants

Shifts in the elemental stoichiometry of organisms in response to their ontogeny and to changing environmental conditions should be related to metabolomic changes because elements operate mostly as parts of molecular compounds. Here we show this relationship in leaves of Erica multiflora throughout their seasonal development and in response to moderate experimental field conditions of drought and warming. The N/P ratio in leaves decreased in the metabolically active growing seasons, coinciding with an increase in the content of primary metabolites. These results support the growth-rate hypothesis that states that rapidly growing organisms present low N/P ratios because of the increase in allocation of P to RNA. The foliar N/K and P/K ratios were lower in summer and in the drought treatment, in accordance with the role of K in osmotic protection, and coincided with the increase of compounds related to the avoidance of water stress. These results provide strong evidence of the relationship between the changes in foliar C/N/P/K stoichiometry and the changes in the leaf's metabolome during plant growth and environmental stress. Thus these results represent a step in understanding the relationships between stoichiometry and an organism's lifestyle.     

Droplet formation and scaling in dense suspensions

When a dense suspension is squeezed from a nozzle, droplet detachment can occur similar to that of pure liquids. While in pure liquids the process of droplet detachment is well characterized through self-similar profiles and known scaling laws, we show here the simple presence of particles causes suspensions to break up in a new fashion. Using high-speed imaging, we find that detachment of a suspension drop is described by a power law; specifically we find the neck minimum radius, r(m), scales like near breakup at time τ = 0. We demonstrate data collapse in a variety of particle/liquid combinations, packing fractions, solvent viscosities, and initial conditions. We argue that this scaling is a consequence of particles deforming the neck surface, thereby creating a pressure that is balanced by inertia, and show how it emerges from topological constraints that relate particle configurations with macroscopic Gaussian curvature. This new type of scaling, uniquely enforced by geometry and regulated by the particles, displays memory of its initial conditions, fails to be self-similar, and has implications for the pressure given at generic suspension interfaces.