The alpha-kinase family: an exceptional branch on the protein kinase tree

The alpha-kinase family represents a class of atypical protein kinases that display little sequence similarity to conventional protein kinases. Early studies on myosin heavy chain kinases in Dictyostelium discoideum revealed their unusual propensity to phosphorylate serine and threonine residues in the context of an alpha-helix. Although recent studies show that some members of this family can also phosphorylate residues in non-helical regions, the name alpha-kinase has remained. During evolution, the alpha-kinase domains combined with many different functional subdomains such as von Willebrand factor-like motifs (vWKa) and even cation channels (TRPM6 and TRPM7). As a result, these kinases are implicated in a large variety of cellular processes such as protein translation, Mg²⁺ homeostasis, intracellular transport, cell migration, adhesion, and proliferation. Here, we review the current state of knowledge on different members of this kinase family and discuss the potential use of alpha-kinases as drug targets in diseases such as cancer.     

6-相步光弹仪测试细纤维/树脂基体相界面剪应力

用新型的6-相步光弹仪,对直径25μm的单玻璃纤维增强环氧树脂复合材料的纤维-树脂相界面微观应力分布进行测试.相步弹性学分析表明纤维末端和纤维断裂处附近的等级条纹级数较高,存在较大的应力集中区域.试样两端加载18.38,25.61和32.53MPa时,纤维末端相界面剪应力最大值分别出现在距纤维末端7,18和33μm处,为26.87,30.22和33.20MPa.纤维断裂处,加载为24.69MPa时,相界面剪应力最大值出现在距纤维断裂25μm处,约30MPa;加载增加到33.09MPa时,高的等级条纹级数区域向远离纤维断裂处延伸,相界面剪应力最大值增加到约36MPa.     

Mobile genetic elements of Staphylococcus aureus

Bacteria such as Staphylococcus aureus are successful as commensal organisms or pathogens in part because they adapt rapidly to selective pressures imparted by the human host. Mobile genetic elements (MGEs) play a central role in this adaptation process and are a means to transfer genetic information (DNA) among and within bacterial species. Importantly, MGEs encode putative virulence factors and molecules that confer resistance to antibiotics, including the gene that confers resistance to beta-lactam antibiotics in methicillin-resistant S. aureus (MRSA). Inasmuch as MRSA infections are a significant problem worldwide and continue to emerge in epidemic waves, there has been significant effort to improve diagnostic assays and to develop new antimicrobial agents for treatment of disease. Our understanding of S. aureus MGEs and the molecules they encode has played an important role toward these ends and has provided detailed insight into the evolution of antimicrobial resistance mechanisms and virulence.     

Two types of muscarinic acetylcholine receptors in Drosophila and other arthropods

Muscarinic acetylcholine receptors (mAChRs) play a central role in the mammalian nervous system. These receptors are G protein-coupled receptors (GPCRs), which are activated by the agonists acetylcholine and muscarine, and blocked by a variety of antagonists. Mammals have five mAChRs (m1–m5). In this study, we cloned two structurally related GPCRs from the fruit fly Drosophila melanogaster, which, after expression in Chinese hamster ovary cells, proved to be muscarinic acetylcholine receptors. One mAChR (the A-type; encoded by gene CG4356) is activated by acetylcholine (EC₅₀, 5 × 10^?8 M) and muscarine (EC₅₀, 6 × 10^?8 M) and blocked by the classical mAChR antagonists atropine, scopolamine, and 3-quinuclidinyl-benzilate (QNB), while the other (the B-type; encoded by gene CG7918) is also activated by acetylcholine, but has a 1,000-fold lower sensitivity to muscarine, and is not blocked by the antagonists. A- and B-type mAChRs were also cloned and functionally characterized from the red flour beetle Tribolium castaneum. Recently, Haga et al. (Nature 2012, 482: 547–551) published the crystal structure of the human m2 mAChR, revealing 14 amino acid residues forming the binding pocket for QNB. These residues are identical between the human m2 and the D. melanogaster and T. castaneum A-type mAChRs, while many of them are different between the human m2 and the B-type receptors. Using bioinformatics, one orthologue of the A-type and one of the B-type mAChRs could also be found in all other arthropods with a sequenced genome. Protostomes, such as arthropods, and deuterostomes, such as mammals and other vertebrates, belong to two evolutionarily distinct lineages of animal evolution that split about 700 million years ago. We found that animals that originated before this split, such as cnidarians (Hydra), had two A-type mAChRs. From these data we propose a model for the evolution of mAChRs.     

New variety of Mentzelia multicaulis (Loasaceae) from the Book Cliffs of Utah

Described is Mentzelia multicaulis (Osterh.) Goodman var. librina Thorne & F. J. Smith.     

Hosts of juniper mistletoe at Walnut Canyon National Monument, Arizona

Four species of junipers, Juniperus osteosperma, J. scopulorum, J. monosperma, and J. deppeana, occur in mixed stands at Walnut Canyon National Monument, Arizona. All are parasitized by Phoradendron juniperinum, but the mistletoe was most common on J. osteosperma and least common on J. scopulorum. Fernbush ( Chamaebatiaria millefolium, Rosaceae) was a very rare host.     

Mechanistic Explanations and Models in Molecular Systems Biology

Mechanistic models in molecular systems biology are generally mathematical models of the action of networks of biochemical reactions, involving metabolism, signal transduction, and/or gene expression. They can be either simulated numerically or analyzed analytically. Systems biology integrates quantitative molecular data acquisition with mathematical models to design new experiments, discriminate between alternative mechanisms and explain the molecular basis of cellular properties. At the heart of this approach are mechanistic models of molecular networks. We focus on the articulation and development of mechanistic models, identifying five constraints which guide the articulation of models in molecular systems biology. These constraints are not independent of one another, with the result that modeling becomes an iterative process. We illustrate the use of these constraints in the modeling of the mechanism for bistability in the lac operon.     

The dynamic disulphide relay of quiescin sulphydryl oxidase

Protein stability, assembly, localization and regulation often depend on the formation of disulphide crosslinks between cysteine side chains. Enzymes known as sulphydryl oxidases catalyse de novo disulphide formation and initiate intra- and intermolecular dithiol/disulphide relays to deliver the disulphides to substrate proteins. Quiescin sulphydryl oxidase (QSOX) is a unique, multi-domain disulphide catalyst that is localized primarily to the Golgi apparatus and secreted fluids and has attracted attention owing to its overproduction in tumours. In addition to its physiological importance, QSOX is a mechanistically intriguing enzyme, encompassing functions typically carried out by a series of proteins in other disulphide-formation pathways. How disulphides are relayed through the multiple redox-active sites of QSOX and whether there is a functional benefit to concatenating these sites on a single polypeptide are open questions. Here we present the first crystal structure of an intact QSOX enzyme, derived from a trypanosome parasite. Notably, sequential sites in the disulphide relay were found more than 40?? apart in this structure, too far for direct disulphide transfer. To resolve this puzzle, we trapped and crystallized an intermediate in the disulphide hand-off, which showed a 165° domain rotation relative to the original structure, bringing the two active sites within disulphide-bonding distance. The comparable structure of a mammalian QSOX enzyme, also presented here, shows further biochemical features that facilitate disulphide transfer in metazoan orthologues. Finally, we quantified the contribution of concatenation to QSOX activity, providing general lessons for the understanding of multi-domain enzymes and the design of new catalytic relays.     

Social networks and cooperation in hunter-gatherers

Social networks show striking structural regularities, and both theory and evidence suggest that networks may have facilitated the development of large-scale cooperation in humans. Here, we characterize the social networks of the Hadza, a population of hunter-gatherers in Tanzania. We show that Hadza networks have important properties also seen in modernized social networks, including a skewed degree distribution, degree assortativity, transitivity, reciprocity, geographic decay and homophily. We demonstrate that Hadza camps exhibit high between-group and low within-group variation in public goods game donations. Network ties are also more likely between people who give the same amount, and the similarity in cooperative behaviour extends up to two degrees of separation. Social distance appears to be as important as genetic relatedness and physical proximity in explaining assortativity in cooperation. Our results suggest that certain elements of social network structure may have been present at an early point in human history. Also, early humans may have formed ties with both kin and non-kin, based in part on their tendency to cooperate. Social networks may thus have contributed to the emergence of cooperation.     

Twenty-first-century warming of a large Antarctic ice-shelf cavity by a redirected coastal current

The Antarctic ice sheet loses mass at its fringes bordering the Southern Ocean. At this boundary, warm circumpolar water can override the continental slope front, reaching the grounding line through submarine glacial troughs and causing high rates of melting at the deep ice-shelf bases. The interplay between ocean currents and continental bathymetry is therefore likely to influence future rates of ice-mass loss. Here we show that a redirection of the coastal current into the Filchner Trough and underneath the Filchner-Ronne Ice Shelf during the second half of the twenty-first century would lead to increased movement of warm waters into the deep southern ice-shelf cavity. Water temperatures in the cavity would increase by more than 2 degrees Celsius and boost average basal melting from 0.2 metres, or 82 billion tonnes, per year to almost 4 metres, or 1,600 billion tonnes, per year. Our results, which are based on the output of a coupled ice-ocean model forced by a range of atmospheric outputs from the HadCM3 climate model, suggest that the changes would be caused primarily by an increase in ocean surface stress in the southeastern Weddell Sea due to thinning of the formerly consolidated sea-ice cover. The projected ice loss at the base of the Filchner-Ronne Ice Shelf represents 80 per cent of the present Antarctic surface mass balance. Thus, the quantification of basal mass loss under changing climate conditions is important for projections regarding the dynamics of Antarctic ice streams and ice shelves, and global sea level rise.