Inhibitory receptors bind ANGPTLs and support blood stem cells and leukaemia development

How environmental cues regulate adult stem cell and cancer cell activity through surface receptors is poorly understood. Angiopoietin-like proteins (ANGPTLs), a family of seven secreted glycoproteins, are known to support the activity of haematopoietic stem cells (HSCs) in vitro and in vivo. ANGPTLs also have important roles in lipid metabolism, angiogenesis and inflammation, but were considered 'orphan ligands' because no receptors were identified. Here we show that the immune-inhibitory receptor human leukocyte immunoglobulin-like receptor B2 (LILRB2) and its mouse orthologue paired immunoglobulin-like receptor (PIRB) are receptors for several ANGPTLs. LILRB2 and PIRB are expressed on human and mouse HSCs, respectively, and the binding of ANGPTLs to these receptors supported ex vivo expansion of HSCs. In mouse transplantation acute myeloid leukaemia models, a deficiency in intracellular signalling of PIRB resulted in increased differentiation of leukaemia cells, revealing that PIRB supports leukaemia development. Our study indicates an unexpected functional significance of classical immune-inhibitory receptors in maintenance of stemness of normal adult stem cells and in support of cancer development.     

Nanotechnology: fundamental research to product development

The concept of an integrated "lab on a chip" has long been a goal for the micro-electro-mechanical-systems(MEMS) community.This would entail the integration of not only the sampling and analysis of various functions,but also the ability to transmit this information off the chip to a central repository.This paper describes the initial steps in the fabrication of a "lab on a chip" which would continually analyze blood sampled via microneedles using techniques such as nano plasmonics,specifically,concentrations of glucose.The analysis could then be transmitted off the chip using digital signal processing.This paper describes the analysis and optimization of the microneedle shape and size and the fabrication of the resulting needles in silicon using deep reactive ion etching(DRIE).The paper also describes the opportunities for fabrication of such needles in alternative materials and describes the issues that still have to be overcome before such an integrated device is realized.     

Thomas Harriot’s optics,between experiment and imagination: the case of Mr Bulkeley’s glass

Some time in the late 1590s, the Welsh amateur mathematician John Bulkeley wrote to Thomas Harriot asking his opinion about the properties of a truly gargantuan (but totally imaginary) plano-spherical convex lens, 48 feet in diameter. While Bulkeley’s original letter is lost, Harriot devoted several pages to the optical properties of “Mr Bulkeley his Glasse” in his optical papers (now in British Library MS Add. 6789), paying particular attention to the place of its burning point. Harriot’s calculational methods in these papers are almost unique in Harriot’s optical remains, in that he uses both the sine law of refraction and interpolation from Witelo’s refraction tables in order to analyze the passage of light through the glass. For this and other reasons, it is very likely that Harriot wrote his papers on Bulkeley’s glass very shortly after his discovery of the law and while still working closely with Witelo’s great Optics; the papers represent, perhaps, his very first application of the law. His and Bulkeley’s interest in this giant glass conform to a long English tradition of curiosity about the optical and burning properties of large glasses, which grew more intense in late sixteenth-century England. In particular, Thomas Digges’s bold and widely known assertions about his father’s glasses that could see things several miles distant and could burn objects a half-mile or further away may have attracted Harriot and Bulkeley’s skeptical attention; for Harriot’s analysis of the burning distance and the intensity of Bulkeley’s fantastic lens, it shows that Digges’s claims could never have been true about any real lens (and this, I propose, was what Bulkeley had asked about in his original letter to Harriot). There was also a deeper, mathematical relevance to the problem that may have caught Harriot’s attention. His most recent source on refraction—Giambattista della Porta’s De refractione of 1593—identified a mathematical flaw in Witelo’s cursory suggestion about the optics of a lens (the only place that lenses appear, however fleetingly, in the writings of the thirteenth-century Perspectivist authors). In his early notes on optics, in a copy of Witelo’s optics, Harriot highlighted Witelo’s remarks on the lens and della Porta’s criticism (which he found unsatisfactory). The most significant problem with Witelo’s theorem would disappear as the radius of curvature of the lens approached infinity. Bulkeley’s gigantic glass, then, may have provided Harriot an opportunity to test out Witelo’s claims about a plano-spherical glass, at a time when he was still intensely concerned with the problems and methods of the Perspectivist school.     

The cyclin-dependent kinase family in the social amoebozoan Dictyostelium discoideum

Cyclin-dependent kinases (Cdk) are a family of serine/threonine protein kinases that regulate eukaryotic cell cycle progression. Their ability to modulate the cell cycle has made them an attractive target for anti-cancer therapies. Cdk protein function has been studied in a variety of Eukaryotes ranging from yeast to humans. In the social amoebozoan Dictyostelium discoideum, several homologues of mammalian Cdks have been identified and characterized. The life cycle of this model organism is comprised of a feeding stage where single cells grow and divide mitotically as they feed on their bacterial food source and a multicellular developmental stage that is induced by starvation. Thus it is a valuable system for studying a variety of cellular and developmental processes. In this review I summarize the current knowledge of the Cdk protein family in Dictyostelium by highlighting the research efforts focused on the characterization of Cdk1, Cdk5, and Cdk8 in this model Eukaryote. Accumulated evidence indicates that each protein performs distinct functions during the Dictyostelium life cycle with Cdk1 being required for growth and Cdk5 and Cdk8 being required for processes that occur during development. Recent studies have shown that Dictyostelium Cdk5 shares attributes with mammalian Cdk5 and that the mammalian Cdk inhibitor roscovitine can be used to inhibit Cdk5 activity in Dictyostelium. Together, these results show that Dictyostelium can be used as a model system for studying Cdk protein function.     

Evaluation of the Heat,Entropy, and Rotational Changes Produced by Gravitational Segregation during Core Formation

Core formation by gravitational segregation allegedly released sufficient interior heat to melt the Earth. Analysis of the energetics, which compare gravitational potential energy (Ug) of a fictitious,...     

Microhabitat selection by the johnny darter, Etheostoma nigrum Rafinesque, in a Wyoming stream

Microhabitat selection by the johnny darter ( Etheostoma nigrum ) was examined in the North Laramie River, Platte County, Wyoming, where it does not occur with other darter species in the same stream reach. Electivity indices based on microhabitat observations indicate that E. nigrum avoids riffles and selects certain microhabitats characterized by intermediate water depths in pools and slow-moving runs with a substrate composed primarily of silt and sand. Niche breadth and electivity values for total depth, bottom water velocity, and substrate measurements from this study indicate that E. nigrum is a habitat generalist, except at the extreme ends of the habitat gradient. Habitat use here is generally similar to other studies where E. nigrum occurred with one or more other darter species. This study found little evidence for competitive release in the absence of other darters.     

Catalytic Z-selective olefin cross-metathesis for natural product synthesis

Alkenes are found in many biologically active molecules, and there are a large number of chemical transformations in which alkenes act as the reactants or products (or both) of the reaction. Many alkenes exist as either the E or the higher-energy Z stereoisomer. Catalytic procedures for the stereoselective formation of alkenes are valuable, yet methods enabling the synthesis of 1,2-disubstituted Z alkenes are scarce. Here we report catalytic Z-selective cross-metathesis reactions of terminal enol ethers, which have not been reported previously, and of allylic amides, used until now only in E-selective processes. The corresponding disubstituted alkenes are formed in up to >98% Z selectivity and 97% yield. These transformations, promoted by catalysts that contain the highly abundant and inexpensive metal molybdenum, are amenable to gram-scale operations. Use of reduced pressure is introduced as a simple and effective strategy for achieving high stereoselectivity. The utility of this method is demonstrated by its use in syntheses of an anti-oxidant plasmalogen phospholipid, found in electrically active tissues and implicated in Alzheimer's disease, and the potent immunostimulant KRN7000.     

The assembly of a GTPase-kinase signalling complex by a bacterial catalytic scaffold

The fidelity and specificity of information flow within a cell is controlled by scaffolding proteins that assemble and link enzymes into signalling circuits. These circuits can be inhibited by bacterial effector proteins that post-translationally modify individual pathway components. However, there is emerging evidence that pathogens directly organize higher-order signalling networks through enzyme scaffolding, and the identity of the effectors and their mechanisms of action are poorly understood. Here we identify the enterohaemorrhagic Escherichia coli O157:H7 type III effector EspG as a regulator of endomembrane trafficking using a functional screen, and report ADP-ribosylation factor (ARF) GTPases and p21-activated kinases (PAKs) as its relevant host substrates. The 2.5?? crystal structure of EspG in complex with ARF6 shows how EspG blocks GTPase-activating-protein-assisted GTP hydrolysis, revealing a potent mechanism of GTPase signalling inhibition at organelle membranes. In addition, the 2.8?? crystal structure of EspG in complex with the autoinhibitory Iα3-helix of PAK2 defines a previously unknown catalytic site in EspG and provides an allosteric mechanism of kinase activation by a bacterial effector. Unexpectedly, ARF and PAKs are organized on adjacent surfaces of EspG, indicating its role as a 'catalytic scaffold' that effectively reprograms cellular events through the functional assembly of GTPase-kinase signalling complex.