MYCN haploinsufficiency is associated with reduced brain size and intestinal atresias in Feingold syndrome

Feingold syndrome is characterized by variable combinations of esophageal and duodenal atresias, microcephaly, learning disability, syndactyly and cardiac defect. We show here that heterozygous mutations in the gene MYCN are present in Feingold syndrome. All mutations are predicted to disrupt both the full-length protein and a new shortened MYCN isoform, suggesting that multiple aspects of early embryogenesis and postnatal brain growth in humans are tightly regulated by MYCN dosage.     

Evolutionary origin and development of snake fangs

Many advanced snakes use fangs-specialized teeth associated with a venom gland-to introduce venom into prey or attacker. Various front- and rear-fanged groups are recognized, according to whether their fangs are positioned anterior (for example cobras and vipers) or posterior (for example grass snakes) in the upper jaw. A fundamental controversy in snake evolution is whether or not front and rear fangs share the same evolutionary and developmental origin. Resolving this controversy could identify a major evolutionary transition underlying the massive radiation of advanced snakes, and the associated developmental events. Here we examine this issue by visualizing the tooth-forming epithelium in the upper jaw of 96 snake embryos, covering eight species. We use the sonic hedgehog gene as a marker, and three-dimensionally reconstruct the development in 41 of the embryos. We show that front fangs develop from the posterior end of the upper jaw, and are strikingly similar in morphogenesis to rear fangs. This is consistent with their being homologous. In front-fanged snakes, the anterior part of the upper jaw lacks sonic hedgehog expression, and ontogenetic allometry displaces the fang from its posterior developmental origin to its adult front position-consistent with an ancestral posterior position of the front fang. In rear-fanged snakes, the fangs develop from an independent posterior dental lamina and retain their posterior position. In light of our findings, we put forward a new model for the evolution of snake fangs: a posterior subregion of the tooth-forming epithelium became developmentally uncoupled from the remaining dentition, which allowed the posterior teeth to evolve independently and in close association with the venom gland, becoming highly modified in different lineages. This developmental event could have facilitated the massive radiation of advanced snakes in the Cenozoic era, resulting in the spectacular diversity of snakes seen today.     

Bipolar supercurrent in graphene

Graphene--a recently discovered form of graphite only one atomic layer thick--constitutes a new model system in condensed matter physics, because it is the first material in which charge carriers behave as massless chiral relativistic particles. The anomalous quantization of the Hall conductance, which is now understood theoretically, is one of the experimental signatures of the peculiar transport properties of relativistic electrons in graphene. Other unusual phenomena, like the finite conductivity of order 4e(2)/h (where e is the electron charge and h is Planck's constant) at the charge neutrality (or Dirac) point, have come as a surprise and remain to be explained. Here we experimentally study the Josephson effect in mesoscopic junctions consisting of a graphene layer contacted by two closely spaced superconducting electrodes. The charge density in the graphene layer can be controlled by means of a gate electrode. We observe a supercurrent that, depending on the gate voltage, is carried by either electrons in the conduction band or by holes in the valence band. More importantly, we find that not only the normal state conductance of graphene is finite, but also a finite supercurrent can flow at zero charge density. Our observations shed light on the special role of time reversal symmetry in graphene, and demonstrate phase coherent electronic transport at the Dirac point.     

The magnetic nature of disk accretion onto black holes

Although disk accretion onto compact objects-white dwarfs, neutron stars and black holes-is central to much of high-energy astrophysics, the mechanisms that enable this process have remained observationally difficult to determine. Accretion disks must transfer angular momentum in order for matter to travel radially inward onto the compact object. Internal viscosity from magnetic processes and disk winds can both in principle transfer angular momentum, but hitherto we lacked evidence that either occurs. Here we report that an X-ray-absorbing wind discovered in an observation of the stellar-mass black hole binary GRO J1655 - 40 (ref. 6) must be powered by a magnetic process that can also drive accretion through the disk. Detailed spectral analysis and modelling of the wind shows that it can only be powered by pressure generated by magnetic viscosity internal to the disk or magnetocentrifugal forces. This result demonstrates that disk accretion onto black holes is a fundamentally magnetic process.     

Mechanistic artefact explanation

One thing about technical artefacts that needs to be explained is how their physical make-up, or structure, enables them to fulfil the behaviour associated with their function, or, more colloquially, how they work. In this paper I develop an account of such explanations based on the familiar notion of mechanistic explanation. To accomplish this, I (1) outline two explanatory strategies that provide two different types of insight into an artefact’s functioning, and (2) show how human action inevitably plays a role in artefact explanation. I then use my own account to criticize other recent work on mechanistic explanation and conclude with some general implications for the philosophy of explanation.     

The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDA) remains a lethal malignancy despite much progress concerning its molecular characterization. PDA tumours harbour four signature somatic mutations in addition to numerous lower frequency genetic events of uncertain significance. Here we use Sleeping Beauty (SB) transposon-mediated insertional mutagenesis in a mouse model of pancreatic ductal preneoplasia to identify genes that cooperate with oncogenic Kras(G12D) to accelerate tumorigenesis and promote progression. Our screen revealed new candidate genes for PDA and confirmed the importance of many genes and pathways previously implicated in human PDA. The most commonly mutated gene was the X-linked deubiquitinase Usp9x, which was inactivated in over 50% of the tumours. Although previous work had attributed a pro-survival role to USP9X in human neoplasia, we found instead that loss of Usp9x enhances transformation and protects pancreatic cancer cells from anoikis. Clinically, low USP9X protein and messenger RNA expression in PDA correlates with poor survival after surgery, and USP9X levels are inversely associated with metastatic burden in advanced disease. Furthermore, chromatin modulation with trichostatin A or 5-aza-2'-deoxycytidine elevates USP9X expression in human PDA cell lines, indicating a clinical approach for certain patients. The conditional deletion of Usp9x cooperated with Kras(G12D) to accelerate pancreatic tumorigenesis in mice, validating their genetic interaction. We propose that USP9X is a major tumour suppressor gene with prognostic and therapeutic relevance in PDA.     

Molecular characterization of <Emphasis Type="Italic">Arabidopsis</Emphasis> PHO80-like proteins,a novel class of CDKA;1-interacting cyclins

Cyclins are regulatory proteins that interact with cyclin-dependent kinases (CDKs) to control progression through the cell cycle. In Arabidopsis thaliana, 34 cyclin genes have been described, grouped into five different types (A, B, D, H, and T). A novel class of seven cyclins was isolated and characterized in Arabidopsis, designated P-type cyclins (CYCPs). They all share a conserved central region of 100 amino acids (cyclin box) displaying homology to the corresponding region of the PHO80 cyclin from Saccharomyces cerevisiae and the related G1 cyclins from Trypanosoma cruzi and T. brucei. The CYCP4;2 gene was able to partially re-establish the phosphate-dependent expression of the PHO5 gene in a pho80 mutant strain of yeast. The CYCPs interact preferentially with CDKA;1 in vivo and in vitro as shown by yeast two-hybrid analysis and co-immunoprecipitation experiments. P-type cyclins were mostly expressed in proliferating cells, albeit also in differentiating and mature tissues. The possible role of CYCPs in linking cell division, cell differentiation, and the nutritional status of the cell is discussed.Received 9 February 2004; received after revision 18 March; accepted 19 April 2004