Physiology: does gut hormone PYY3-36 decrease food intake in rodents?

Batterham et al. report that the gut peptide hormone PYY3-36 decreases food intake and body-weight gain in rodents, a discovery that has been heralded as potentially offering a new therapy for obesity. However, we have been unable to replicate their results. Although the reasons for this discrepancy remain undetermined, an effective anti-obesity drug ultimately must produce its effects across a range of situations. The fact that the findings of Batterham et al. cannot easily be replicated calls into question the potential value of an anti-obesity approach that is based on administration of PYY3-36.     

岩板变形破坏过程加载装置设计及试验验证

浅埋采空区顶板变形破坏过程与灾变机理研究,是目前下伏采空区建(构)筑物工程实践中急待解决的难题。针对国内外在岩板变形破坏试验中存在的不足,自行研发了能够进行岩石类材料矩形板弯曲试验的加载装置。利用MTS岩石力学试验机和研发的加载装置,对单层岩板断裂铰接成拱的过程及其失稳机理进行了分析,并对双层组合岩板进行了变形破坏过程的试验研究。试验结果表明:随着施加荷载的不断增大,单层岩板梁式断裂后铰接形成拱形结构,并在铰接点产生水平反力。双层组合岩板的上层板存在梁式断裂、拱形破坏和板式断裂破坏3种破坏模式。单层岩板和双层岩板的荷载-位移全过程曲线,均存在4个明显的力学响应阶段,并由该曲线分析了岩拱结构形成过程及其失稳的特征。     

Human IgE, IgG4 and resistance to reinfection with Schistosoma haematobium

A well recognized feature of the immune response to parasitic helminth infections, including schistosomiasis, is the production of large amounts of specific and nonspecific IgE1,2. Immunological pathways involving IgE can lead to damage to the developing schistosomulum and it has been suggested that responses involving IgE could have evolved as protection against helminth infections. There has been no epidemiological evidence to support this idea and the only significant IgE responses known in man are those involved in the pathogenesis of allergic disease. Here we measure serological response during reinfection with S. haematobium and demonstrate that IgE antibodies in man can be beneficial. Our results support the hypothesis that the slow build-up of IgE to high levels and the early production of IgG4 antibodies, which may block IgE pathways are responsible for delaying the development of protective immunity to S. haematobium.     

A systematic, genome-wide, phenotype-driven mutagenesis programme for gene function studies in the mouse

As the human genome project approaches completion, the challenge for mammalian geneticists is to develop approaches for the systematic determination of mammalian gene function. Mouse mutagenesis will be a key element of studies of gene function. Phenotype-driven approaches using the chemical mutagen ethylnitrosourea (ENU) represent a potentially efficient route for the generation of large numbers of mutant mice that can be screened for novel phenotypes. The advantage of this approach is that, in assessing gene function, no a priori assumptions are made about the genes involved in any pathway. Phenotype-driven mutagenesis is thus an effective method for the identification of novel genes and pathways. We have undertaken a genome-wide, phenotype-driven screen for dominant mutations in the mouse. We generated and screened over 26,000 mice, and recovered some 500 new mouse mutants. Our work, along with the programme reported in the accompanying paper, has led to a substantial increase in the mouse mutant resource and represents a first step towards systematic studies of gene function in mammalian genetics.     

Reconfigurable self-assembly through chiral control of interfacial tension

From determining the optical properties of simple molecular crystals to establishing the preferred handedness in highly complex vertebrates, molecular chirality profoundly influences the structural, mechanical and optical properties of both synthetic and biological matter on macroscopic length scales. In soft materials such as amphiphilic lipids and liquid crystals, the competition between local chiral interactions and global constraints imposed by the geometry of the self-assembled structures leads to frustration and the assembly of unique materials. An example of particular interest is smectic liquid crystals, where the two-dimensional layered geometry cannot support twist and chirality is consequently expelled to the edges in a manner analogous to the expulsion of a magnetic field from superconductors. Here we demonstrate a consequence of this geometric frustration that leads to a new design principle for the assembly of chiral molecules. Using a model system of colloidal membranes, we show that molecular chirality can control the interfacial tension, an important property of multi-component mixtures. This suggests an analogy between chiral twist, which is expelled to the edges of two-dimensional membranes, and amphiphilic surfactants, which are expelled to oil-water interfaces. As with surfactants, chiral control of interfacial tension drives the formation of many polymorphic assemblages such as twisted ribbons with linear and circular topologies, starfish membranes, and double and triple helices. Tuning molecular chirality in situ allows dynamical control of line tension, which powers polymorphic transitions between various chiral structures. These findings outline a general strategy for the assembly of reconfigurable chiral materials that can easily be moved, stretched, attached to one another and transformed between multiple conformational states, thus allowing precise assembly and nanosculpting of highly dynamical and designable materials with complex topologies.     

Kinesin-related cut7 protein associates with mitotic and meiotic spindles in fission yeast.

Several mitotic and meiotic gene products are related to the microtubule motor kinesin, providing insight into the molecular basis of the complex motile events responsible for spindle formation and function. Of these genes, three have been shown to affect spindle structure when mutated. The most severe phenotype is seen in Aspergillus nidulans bimC and Schizosaccharomyces pombe cut7 mutants. In both fungi the intranuclear spindle is bipolar, with microtubules that emanate from spindle pole bodies at either pole, interdigitating in a central overlap zone. In bimC and cut7 mutants, microtubule interdigitation does not appear to take place, instead two unconnected half spindles form and chromosome separation fails. Here we report that cut7 protein concentrates on or near the spindle pole bodies throughout mitotic and meiotic nuclear division and associates with mitotic spindle microtubules in a stage-specific manner, associating with the mid-anaphase B midzone. In cut7ts mutants, spindle pole bodies stain but mitotic microtubules do not.     

Human Alu element retrotransposition induced by genotoxic stress

Alu elements are found exclusively in primate species and comprise over 10% of the human genome. To better define the mechanisms responsible for Alu replication, we introduced a human Alu element into mouse cells. We report that Alu retrotransposition can be induced in mouse cells by exposure to the topoisomerase II inhibitor etoposide and is mediated in trans by endogenous mouse long interspersed elements (LINEs).     

Novel potential mitotic motor protein encoded by the fission yeast cut7+ gene

The structure equivalent to higher eukaryotic centrosomes in fission yeast, the nuclear membrane-bound spindle pole body, is inactive during interphase. On transition from G2 to M phase of the cell cycle, the spindle pole body duplicates; the daughter pole bodies seed microtubules which interdigitate to form a short spindle that elongates to span the nucleus at metaphase. We have identified two loci which, when mutated, block spindle formation. The predicted product of one of these genes, cut7+, contains an amino-terminal domain similar to the kinesin heavy chain head domain, indicating that the cut7+ product could be a spindle motor. The cut7+ gene resembles the Aspergillus nidulans putative spindle motor gene bimC, both in terms of its organization with a homologous amino-terminal head and no obvious heptad repeats and in the morphology of the mutant phenotype. But we find no similarity between the carboxy termini of these genes, suggested that either the cut7+ gene represents a new class of kinesin genes and that fission yeast may in addition contain a bimC homologue, or that the carboxy termini of these mitotic kinesins are not evolutionarily conserved and that the cut7+ gene belongs to a subgroup of bimC-related kinesins.     

The mechanosensory protein MEC-6 is a subunit of the C. elegans touch-cell degenerin channel

Mechanosensory transduction in touch receptor neurons is believed to be mediated by DEG/ENaC (degenerin/epithelial Na+ channel) proteins in nematodes and mammals. In the nematode Caenorhabditis elegans, gain-of-function mutations in the degenerin genes mec-4 and mec-10 (denoted mec-4(d) and mec-10(d), respectively) cause degeneration of the touch cells. This phenotype is completely suppressed by mutation in a third gene, mec-6 (refs 3, 4), that is needed for touch sensitivity. This last gene is also required for the function of other degenerins. Here we show that mec-6 encodes a single-pass membrane-spanning protein with limited similarity to paraoxonases, which are implicated in human coronary heart disease. This gene is expressed in muscle cells and in many neurons, including the six touch receptor neurons. MEC-6 increases amiloride-sensitive Na+ currents produced by MEC-4(d)/MEC-10(d) by approximately 30-fold, and functions synergistically with MEC-2 (a stomatin-like protein that regulates MEC-4(d)/MEC-10(d) channel activity) to increase the currents by 200-fold. MEC-6 physically interacts with all three channel proteins. In vivo, MEC-6 co-localizes with MEC-4, and is required for punctate MEC-4 expression along touch-neuron processes. We propose that MEC-6 is a part of the degenerin channel complex that may mediate mechanotransduction in touch cells.