Postnatal loss of Dlk1 imprinting in stem cells and niche astrocytes regulates neurogenesis

The gene for the atypical NOTCH ligand delta-like homologue 1 (Dlk1) encodes membrane-bound and secreted isoforms that function in several developmental processes in vitro and in vivo. Dlk1, a member of a cluster of imprinted genes, is expressed from the paternally inherited chromosome. Here we show that mice that are deficient in Dlk1 have defects in postnatal neurogenesis in the subventricular zone: a developmental continuum that results in depletion of mature neurons in the olfactory bulb. We show that DLK1 is secreted by niche astrocytes, whereas its membrane-bound isoform is present in neural stem cells (NSCs) and is required for the inductive effect of secreted DLK1 on self-renewal. Notably, we find that there is a requirement for Dlk1 to be expressed from both maternally and paternally inherited chromosomes. Selective absence of Dlk1 imprinting in both NSCs and niche astrocytes is associated with postnatal acquisition of DNA methylation at the germ-line-derived imprinting control region. The results emphasize molecular relationships between NSCs and the niche astrocyte cells of the microenvironment, identifying a signalling system encoded by a single gene that functions coordinately in both cell types. The modulation of genomic imprinting in a stem-cell environment adds a new level of epigenetic regulation to the establishment and maintenance of the niche, raising wider questions about the adaptability, function and evolution of imprinting in specific developmental contexts.     

Resistance to change—A monitor of new technology

This paper examines the credibility of the deficit model of resistance to change in a case study on office automation. A functional analysis of resistance to change is conducted using narrative interviews and documentary analysis. Resistance to change is shown to occur and to affect the implementation process: resistance is identified as a useful source of information, directing the attention of the change agency to improve hardware, software, and the organization. User attitudes were found to change: global skepticism developed into critical acceptance of the office system. The decision-making criteria changed during the 3-year period of the case study. More criteria were used, with user-friendliness becoming more prominent in the decision criteria. The case highlights some limitations of Lewinian field theory in studying resistance to change. Systems theory may provide a more useful framework, organized around the principle that resistance to change is a functional selfmonitoring subsystem guiding the internal adjustment of the changing organization and thus securing effectiveness. This approach may have wider implications for the analysis of social change.     

Taxonomy Based Models for Reasoning: Making Inferences from Electronic Road Sign Information

Taxonomy Based modeling was applied to describe drivers’ mental models of variable message signs (VMS’s) displayed on expressways. Progress in road telematics has made it possible to introduce variable message signs (VMS’s). Sensors embedded in the carriageway every 500m record certain variables (speed, flow rate, etc.) that are transformed in real time into “driving times” to a given destination if road conditions do not change. VMS systems are auto-regulative Man-Machine (AMMI) systems which incorporate a model of the user: if the traffic flow is too high, then drivers should choose alternative routes. In so doing, the traffic flow should decrease. The model of the user is based on suppositions such as: people do not like to waste time, they fully understand the displayed messages, they trust the displayed values, they know of alternative routes. However, people also have a model of the way the system functions. And if they do not believe the contents of the message, they will not act as expected. We collected data through interviews with drivers using the critical incidents technique (Flanagan, 1985). Results show that the mental models that drivers have of the way the VMS system works are various but not numerous and that most of them differ from the“ideal expert” mental model. It is clear that users don’t have an adequate model of how the VMS system works and that VMS planners have a model of user behaviour that does not correspond to the behaviour of the drivers we interviewed. Finally, Taxonomy Based Modeling is discussed as a tool for mental model remediation.     

Mutations in the gene encoding epsilon-sarcoglycan cause myoclonus-dystonia syndrome

The dystonias are a common clinically and genetically heterogeneous group of movement disorders. More than ten loci for inherited forms of dystonia have been mapped, but only three mutated genes have been identified so far. These are DYT1, encoding torsin A and mutant in the early-onset generalized form, GCH1 (formerly known as DYT5), encoding GTP-cyclohydrolase I and mutant in dominant dopa-responsive dystonia, and TH, encoding tyrosine hydroxylase and mutant in the recessive form of the disease. Myoclonus-dystonia syndrome (MDS; DYT11) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21 (refs. 11-13). Using a positional cloning approach, we have identified five different heterozygous loss-of-function mutations in the gene for epsilon-sarcoglycan (SGCE), which we mapped to a refined critical region of about 3.2 Mb. SGCE is expressed in all brain regions examined. Pedigree analysis shows a marked difference in penetrance depending on the parental origin of the disease allele. This is indicative of a maternal imprinting mechanism, which has been demonstrated in the mouse epsilon-sarcoglycan gene.     

CREB regulates hepatic gluconeogenesis through the coactivator PGC-1

When mammals fast, glucose homeostasis is achieved by triggering expression of gluconeogenic genes in response to glucagon and glucocorticoids. The pathways act synergistically to induce gluconeogenesis (glucose synthesis), although the underlying mechanism has not been determined. Here we show that mice carrying a targeted disruption of the cyclic AMP (cAMP) response element binding (CREB) protein gene, or overexpressing a dominant-negative CREB inhibitor, exhibit fasting hypoglycaemia [corrected] and reduced expression of gluconeogenic enzymes. CREB was found to induce expression of the gluconeogenic programme through the nuclear receptor coactivator PGC-1, which is shown here to be a direct target for CREB regulation in vivo. Overexpression of PGC-1 in CREB-deficient mice restored glucose homeostasis and rescued expression of gluconeogenic genes. In transient assays, PGC-1 potentiated glucocorticoid induction of the gene for phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in gluconeogenesis. PGC-1 promotes cooperativity between cyclic AMP and glucocorticoid signalling pathways during hepatic gluconeogenesis. Fasting hyperglycaemia is strongly correlated with type II diabetes, so our results suggest that the activation of PGC-1 by CREB in liver contributes importantly to the pathogenesis of this disease.     

Proteome survey reveals modularity of the yeast cell machinery

Protein complexes are key molecular entities that integrate multiple gene products to perform cellular functions. Here we report the first genome-wide screen for complexes in an organism, budding yeast, using affinity purification and mass spectrometry. Through systematic tagging of open reading frames (ORFs), the majority of complexes were purified several times, suggesting screen saturation. The richness of the data set enabled a de novo characterization of the composition and organization of the cellular machinery. The ensemble of cellular proteins partitions into 491 complexes, of which 257 are novel, that differentially combine with additional attachment proteins or protein modules to enable a diversification of potential functions. Support for this modular organization of the proteome comes from integration with available data on expression, localization, function, evolutionary conservation, protein structure and binary interactions. This study provides the largest collection of physically determined eukaryotic cellular machines so far and a platform for biological data integration and modelling.     

The abundances of constituents of Titan's atmosphere from the GCMS instrument on the Huygens probe

Saturn's largest moon, Titan, remains an enigma, explored only by remote sensing from Earth, and by the Voyager and Cassini spacecraft. The most puzzling aspects include the origin of the molecular nitrogen and methane in its atmosphere, and the mechanism(s) by which methane is maintained in the face of rapid destruction by photolysis. The Huygens probe, launched from the Cassini spacecraft, has made the first direct observations of the satellite's surface and lower atmosphere. Here we report direct atmospheric measurements from the Gas Chromatograph Mass Spectrometer (GCMS), including altitude profiles of the constituents, isotopic ratios and trace species (including organic compounds). The primary constituents were confirmed to be nitrogen and methane. Noble gases other than argon were not detected. The argon includes primordial 36Ar, and the radiogenic isotope 40Ar, providing an important constraint on the outgassing history of Titan. Trace organic species, including cyanogen and ethane, were found in surface measurements.     

A precision measurement of the mass of the top quark

The standard model of particle physics contains parameters--such as particle masses--whose origins are still unknown and which cannot be predicted, but whose values are constrained through their interactions. In particular, the masses of the top quark (M(t)) and W boson (M(W)) constrain the mass of the long-hypothesized, but thus far not observed, Higgs boson. A precise measurement of M(t) can therefore indicate where to look for the Higgs, and indeed whether the hypothesis of a standard model Higgs is consistent with experimental data. As top quarks are produced in pairs and decay in only about 10(-24) s into various final states, reconstructing their masses from their decay products is very challenging. Here we report a technique that extracts more information from each top-quark event and yields a greatly improved precision (of +/- 5.3 GeV/c2) when compared to previous measurements. When our new result is combined with our published measurement in a complementary decay mode and with the only other measurements available, the new world average for M(t) becomes 178.0 +/- 4.3 GeV/c2. As a result, the most likely Higgs mass increases from the experimentally excluded value of 96 to 117 GeV/c2, which is beyond current experimental sensitivity. The upper limit on the Higgs mass at the 95% confidence level is raised from 219 to 251 GeV/c2.     

Superconductivity in diamond

Diamond is an electrical insulator well known for its exceptional hardness. It also conducts heat even more effectively than copper, and can withstand very high electric fields. With these physical properties, diamond is attractive for electronic applications, particularly when charge carriers are introduced (by chemical doping) into the system. Boron has one less electron than carbon and, because of its small atomic radius, boron is relatively easily incorporated into diamond; as boron acts as a charge acceptor, the resulting diamond is effectively hole-doped. Here we report the discovery of superconductivity in boron-doped diamond synthesized at high pressure (nearly 100,000 atmospheres) and temperature (2,500-2,800 K). Electrical resistivity, magnetic susceptibility, specific heat and field-dependent resistance measurements show that boron-doped diamond is a bulk, type-II superconductor below the superconducting transition temperature T(c) approximately 4 K; superconductivity survives in a magnetic field up to Hc2(0) > or = 3.5 T. The discovery of superconductivity in diamond-structured carbon suggests that Si and Ge, which also form in the diamond structure, may similarly exhibit superconductivity under the appropriate conditions.