The protein-protein interaction map of Helicobacter pylori

With the availability of complete DNA sequences for many prokaryotic and eukaryotic genomes, and soon for the human genome itself, it is important to develop reliable proteome-wide approaches for a better understanding of protein function. As elementary constituents of cellular protein complexes and pathways, protein-protein interactions are key determinants of protein function. Here we have built a large-scale protein-protein interaction map of the human gastric pathogen Helicobacter pylori. We have used a high-throughput strategy of the yeast two-hybrid assay to screen 261 H. pylori proteins against a highly complex library of genome-encoded polypeptides. Over 1,200 interactions were identified between H. pylori proteins, connecting 46.6% of the proteome. The determination of a reliability score for every single protein-protein interaction and the identification of the actual interacting domains permitted the assignment of unannotated proteins to biological pathways.     

Mouse models for Friedreich ataxia exhibit cardiomyopathy, sensory nerve defect and Fe-S enzyme deficiency followed by intramitochondrial iron deposits

Friedreich ataxia (FRDA), the most common autosomal recessive ataxia, is characterized by degeneration of the large sensory neurons and spinocerebellar tracts, cardiomyopathy and increased incidence in diabetes. FRDA is caused by severely reduced levels of frataxin, a mitochondrial protein of unknown function. Yeast knockout models as well as histological and biochemical data from heart biopsies or autopsies of FRDA patients have shown that frataxin defects cause a specific iron-sulfur protein deficiency and intramitochondrial iron accumulation. We have recently shown that complete absence of frataxin in the mouse leads to early embryonic lethality, demonstrating an important role for frataxin during mouse development. Through a conditional gene-targeting approach, we have generated in parallel a striated muscle frataxin-deficient line and a neuron/cardiac muscle frataxin-deficient line, which together reproduce important progressive pathophysiological and biochemical features of the human disease: cardiac hypertrophy without skeletal muscle involvement, large sensory neuron dysfunction without alteration of the small sensory and motor neurons, and deficient activities of complexes I-III of the respiratory chain and of the aconitases. Our models demonstrate time-dependent intramitochondrial iron accumulation in a frataxin-deficient mammal, which occurs after onset of the pathology and after inactivation of the Fe-S-dependent enzymes. These mutant mice represent the first mammalian models to evaluate treatment strategies for the human disease.     

Low-dose radiation accelerates aging of the T-cell receptor repertoire in CBA/Ca mice

While the biological effects of high-dose-ionizing radiation on human health are well characterized, the consequences of low-dose radiation exposure remain poorly defined, even though they are of major importance for radiological protection. Lymphocytes are very radiosensitive, and radiation-induced health effects may result from immune cell loss and/or immune system impairment. To decipher the mechanisms of effects of low doses, we analyzed the modulation of the T-cell receptor gene repertoire in mice exposed to a single low (0.1 Gy) or high (1 Gy) dose of radiation. High-throughput T-cell receptor gene profiling was used to visualize T-lymphocyte dynamics over time in control and irradiated mice. Radiation exposure induces “aging-like” effects on the T-cell receptor gene repertoire, detectable as early as 1 month post-exposure and for at least 6 months. Surprisingly, these effects are more pronounced in animals exposed to 0.1 Gy than to 1 Gy, where partial correction occurs over time. Importantly, we found that low-dose radiation effects are partially due to the hematopoietic stem cell impairment. Collectively, our findings show that acute low-dose radiation exposure specifically results in long-term alterations of the T-lymphocyte repertoire.     

Swedenborg's Lunars

The celebrated Swedish natural philosopher and visionary theologian Emanuel Swedenborg (1688–1772) devoted major efforts to the establishment of a reliable method for the determination of longitude at sea. He first formulated a method, based on the astronomical observation of lunar position, while in London in 1710–12. He issued various versions of the method, both in Latin and in Swedish, throughout his career. In 1766, at the age of 78, he presented his scheme for judgment by the Board of Longitude in London. The rich archive of Swedenborg's career allows an unusually detailed historical analysis of his longitude project, an analysis rather better documented than that available for the host of contemporary projectors who launched longitude schemes, submitted their proposals to the Board of Longitude, and have too often been ignored or dismissed by historians. This analysis uses the longitude work to illuminate key aspects of Swedenborg's wider enterprises, including his scheme to set up an astronomical observatory in southern Sweden to be devoted to lunar and stellar observation, his complex attitude to astronomical and magnetic cosmology, and his attempt to fit the notion of longitude into his visionary world-view. Swedenborg's programme also helps make better sense of the metropolitan and international networks of diplomatic and natural philosophical communication in which the longitude schemes were developed and judged. It emerges that his longitude method owed much to the established principles of earlier Baroque and Jesuit natural philosophy while his mature cosmology sought a rational and enlightened model of the universe.     

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.     

Laser cooling of a nanomechanical oscillator into its quantum ground state

The simple mechanical oscillator, canonically consisting of a coupled mass-spring system, is used in a wide variety of sensitive measurements, including the detection of weak forces and small masses. On the one hand, a classical oscillator has a well-defined amplitude of motion; a quantum oscillator, on the other hand, has a lowest-energy state, or ground state, with a finite-amplitude uncertainty corresponding to zero-point motion. On the macroscopic scale of our everyday experience, owing to interactions with its highly fluctuating thermal environment a mechanical oscillator is filled with many energy quanta and its quantum nature is all but hidden. Recently, in experiments performed at temperatures of a few hundredths of a kelvin, engineered nanomechanical resonators coupled to electrical circuits have been measured to be oscillating in their quantum ground state. These experiments, in addition to providing a glimpse into the underlying quantum behaviour of mesoscopic systems consisting of billions of atoms, represent the initial steps towards the use of mechanical devices as tools for quantum metrology or as a means of coupling hybrid quantum systems. Here we report the development of a coupled, nanoscale optical and mechanical resonator formed in a silicon microchip, in which radiation pressure from a laser is used to cool the mechanical motion down to its quantum ground state (reaching an average phonon occupancy number of 0.85 ± 0.08). This cooling is realized at an environmental temperature of 20?K, roughly one thousand times larger than in previous experiments and paves the way for optical control of mesoscale mechanical oscillators in the quantum regime.     

Evolved structure of language shows lineage-specific trends in word-order universals

Languages vary widely but not without limit. The central goal of linguistics is to describe the diversity of human languages and explain the constraints on that diversity. Generative linguists following Chomsky have claimed that linguistic diversity must be constrained by innate parameters that are set as a child learns a language. In contrast, other linguists following Greenberg have claimed that there are statistical tendencies for co-occurrence of traits reflecting universal systems biases, rather than absolute constraints or parametric variation. Here we use computational phylogenetic methods to address the nature of constraints on linguistic diversity in an evolutionary framework. First, contrary to the generative account of parameter setting, we show that the evolution of only a few word-order features of languages are strongly correlated. Second, contrary to the Greenbergian generalizations, we show that most observed functional dependencies between traits are lineage-specific rather than universal tendencies. These findings support the view that-at least with respect to word order-cultural evolution is the primary factor that determines linguistic structure, with the current state of a linguistic system shaping and constraining future states.