Ube3a,the E3 ubiquitin ligase causing Angelman syndrome and linked to autism,regulates protein homeostasis through the proteasomal shuttle Rpn10

Ubiquitination, the covalent attachment of ubiquitin to a target protein, regulates most cellular processes and is involved in several neurological disorders. In particular, Angelman syndrome and one of the most common genomic forms of autism, dup15q, are caused respectively by lack of or excess of UBE3A, a ubiquitin E3 ligase. Its Drosophila orthologue, Ube3a, is also active during brain development. We have now devised a protocol to screen for substrates of this particular ubiquitin ligase. In a neuronal cell system, we find direct ubiquitination by Ube3a of three proteasome-related proteins Rpn10, Uch-L5, and CG8209, as well as of the ribosomal protein Rps10b. Only one of these, Rpn10, is targeted for degradation upon ubiquitination by Ube3a, indicating that degradation might not be the only effect of Ube3a on its substrates. Furthermore, we report the genetic interaction in vivo between Ube3a and the C-terminal part of Rpn10. Overexpression of these proteins leads to an enhanced accumulation of ubiquitinated proteins, further supporting the biochemical evidence of interaction obtained in neuronal cells.     

Acetylation-dependent regulation of endothelial Notch signalling by the SIRT1 deacetylase

Notch signalling is a key intercellular communication mechanism that is essential for cell specification and tissue patterning, and which coordinates critical steps of blood vessel growth. Although subtle alterations in Notch activity suffice to elicit profound differences in endothelial behaviour and blood vessel formation, little is known about the regulation and adaptation of endothelial Notch responses. Here we report that the NAD(+)-dependent deacetylase SIRT1 acts as an intrinsic negative modulator of Notch signalling in endothelial cells. We show that acetylation of the Notch1 intracellular domain (NICD) on conserved lysines controls the amplitude and duration of Notch responses by altering NICD protein turnover. SIRT1 associates with NICD and functions as a NICD deacetylase, which opposes the acetylation-induced NICD stabilization. Consequently, endothelial cells lacking SIRT1 activity are sensitized to Notch signalling, resulting in impaired growth, sprout elongation and enhanced Notch target gene expression in response to DLL4 stimulation, thereby promoting a non-sprouting, stalk-cell-like phenotype. In vivo, inactivation of Sirt1 in zebrafish and mice causes reduced vascular branching and density as a consequence of enhanced Notch signalling. Our findings identify reversible acetylation of the NICD as a molecular mechanism to adapt the dynamics of Notch signalling, and indicate that SIRT1 acts as rheostat to fine-tune endothelial Notch responses.     

Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome

3MC syndrome has been proposed as a unifying term encompassing the overlapping Carnevale, Mingarelli, Malpuech and Michels syndromes. These rare autosomal recessive disorders exhibit a spectrum of developmental features, including characteristic facial dysmorphism, cleft lip and/or palate, craniosynostosis, learning disability and genital, limb and vesicorenal anomalies. Here we studied 11 families with 3MC syndrome and identified two mutated genes, COLEC11 and MASP1, both of which encode proteins in the lectin complement pathway (collectin kidney 1 (CL-K1) and MASP-1 and MASP-3, respectively). CL-K1 is highly expressed in embryonic murine craniofacial cartilage, heart, bronchi, kidney and vertebral bodies. Zebrafish morphants for either gene develop pigmentary defects and severe craniofacial abnormalities. Finally, we show that CL-K1 serves as a guidance cue for neural crest cell migration. Together, these findings demonstrate a role for complement pathway factors in fundamental developmental processes and in the etiology of 3MC syndrome.     

Ordinary language philosophy,explanation, and the historical turn in philosophy of science

Taking a cue from remarks Thomas Kuhn makes in 1990 about the historical turn in philosophy of science, I examine the history of history and philosophy of science within parts of the British philosophical context in the 1950s and early 1960s. During this time, ordinary language philosophy's influence was at its peak. I argue that the ordinary language philosophers' methodological recommendation to analyze actual linguistic practice influences several prominent criticisms of the deductive-nomological model of scientific explanation and that these criticisms relate to the historical turn in philosophy of science. To show these connections, I primarily examine the work of Stephen Toulmin, who taught at Oxford from 1949 to 1954, and Michael Scriven, who completed a dissertation on explanation under Gilbert Ryle and R.B. Braithwaite in 1956. I also consider Mary Hesse's appeal to an ordinary language-influenced account of meaning in her account of the role of models and analogies in scientific reasoning, and W.H. Watson's Wittgensteinian philosophy of science, an early influence on Toulmin. I think there are two upshots to my historical sketch. First, it fills out details of the move away from logical positivism to more historical- and practice-focused philosophies of science. Second, questions about linguistic meaning and the proper targets and aims of philosophical analysis are part and parcel of the historical turn, as well as its reception. Looking at the philosophical background during which so-called linguistic philosophers also had a hand in bringing these questions to prominence helps us understand why.     

The impact on microtubule network of a bracovirus IκB-like protein

Polydnavirus-encoded IκB-like proteins are similar to insect and mammalian IκB, and an immunosuppressive function in the host cells has been inferred to these proteins. Here we show that the expression of one of these IκB-like viral genes, the TnBVank1, in the Drosophila germline affects the localization of gurken, bicoid, and oskar mRNAs whose gene products are relevant for proper embryonic patterning. The altered localization of these mRNAs is suggestive of general defects in the intracellular, microtubule-based, trafficking routes. Analysis of microtubule motor proteins components such as the dynein heavy chain and the kinesin heavy chain revealed defects in the polarized microtubule network. Interestingly, the TnBVANK1 viral protein is uniformly distributed over the entire oocyte cortex, and appears to be anchored to the microtubule ends. Our data open up a very interesting issue on novel function(s) played by the ank gene family by interfering with cytoskeleton organization.     

Hans Reichenbach's and C.I. Lewis's Kantian philosophies of science

Recent work in the history of philosophy of science details the Kantianism of philosophers often thought opposed to one another, e.g., Hans Reichenbach, C.I. Lewis, Rudolf Carnap, and Thomas Kuhn. Historians of philosophy of science in the last two decades have been particularly interested in the Kantianism of Reichenbach, Carnap, and Kuhn, and more recently, of Lewis. While recent historical work focuses on recovering the threatened-to-be-forgotten Kantian themes of early twentieth-century philosophy of science, we should not elide the differences between the Kantian strands running throughout this work. In this paper, I disentangle a few of these strands in the work of Reichenbach and Lewis focusing especially on their theories of relativized, constitutive a priori principles in empirical knowledge. In particular, I highlight three related differences between Reichenbach and Lewis concerning their motivations in analyzing scientific knowledge and scientific practice, their differing conceptions of constitutivity, and their relativization of constitutive a priori principles. In light of these differences, I argue Lewis's Kantianism is more similar to Kuhn's Kantianism than Reichenbach's, and so might be of more contemporary relevance to social and practice-based approaches to the philosophy of science.     

Environmental biosafety and transgenic potato in a centre of diversity for this crop

The Nuffield Council on Bioethics suggests that introgression of genetic material into related species in centres of crop biodiversity is an insufficient justification to bar the use of genetically modified crops in the developing world. They consider that a precautionary approach to forgo the possible benefits invokes the fallacy of thinking that doing nothing is itself without risk to the poor. Here we report findings relevant to this and other aspects of environmental biosafety for genetically modified potato in its main centre of biodiversity, the central Andes. We studied genetically modified potato clones that provide resistance to nematodes, principal pests of Andean potato crops. We show that there is no harm to many non-target organisms, but gene flow occurs to wild relatives growing near potato crops. If stable introgression were to result, the fitness of these wild species could be altered. We therefore transformed the male sterile cultivar Revolucion to provide a genetically modified nematode-resistant potato to evaluate the benefits that this provides until the possibility of stable introgression to wild relatives is determined. Thus, scientific progress is possible without compromise to the precautionary principle.     

Observing brownian motion in vibration-fluidized granular matter

Observation of the rotational brownian motion of a very fine wire immersed in a gas led to one of the most important ideas of equilibrium statistical mechanics. Namely, the many-particle problem of a large number of molecules colliding with the wire can be represented by just two macroscopic parameters: viscosity and temperature. Interest has arisen in the question of whether this idea (mathematically developed in the Langevin model and the fluctuation-dissipation theorem) can also be used to describe systems that are far from equilibrium. Here we report an experimental investigation of an archetypal non-equilibrium system, involving a sensitive torsion oscillator immersed in a granular system of millimetre-size grains that are fluidized by strong external vibrations. The vibro-fluidized granular medium is a driven environment, with continuous injection and dissipation of energy, and the immersed oscillator can be seen as analogous to an elastically bound brownian particle. By measuring the noise and the susceptibility, we show that the experiment can be treated (to a first approximation) with the equilibrium formalism. This gives experimental access to a granular viscosity and an effective temperature; however, these quantities are anisotropic and inhomogeneous. Surprisingly, the vibro-fluidized granular matter behaves as a 'thermal' bath satisfying a fluctuation-dissipation relation.