Showing papers by "University of Geneva published in 2006"

Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints

Abstract: Recent studies have indicated the existence of tumorigenesis barriers that slow or inhibit the progression of preneoplastic lesions to neoplasia. One such barrier involves DNA replication stress, which leads to activation of the DNA damage checkpoint and thereby to apoptosis or cell cycle arrest, whereas a second barrier is mediated by oncogene-induced senescence. The relationship between these two barriers, if any, has not been elucidated. Here we show that oncogene-induced senescence is associated with signs of DNA replication stress, including prematurely terminated DNA replication forks and DNA double-strand breaks. Inhibiting the DNA double-strand break response kinase ataxia telangiectasia mutated (ATM) suppressed the induction of senescence and in a mouse model led to increased tumour size and invasiveness. Analysis of human precancerous lesions further indicated that DNA damage and senescence markers cosegregate closely. Thus, senescence in human preneoplastic lesions is a manifestation of oncogene-induced DNA replication stress and, together with apoptosis, provides a barrier to malignant progression.

International Trial of the Edmonton Protocol for Islet Transplantation

Abstract: Background Islet transplantation offers the potential to improve glycemic control in a subgroup of patients with type 1 diabetes mellitus who are disabled by refractory hypoglycemia. We conducted an international, multicenter trial to explore the feasibility and reproducibility of islet transplantation with the use of a single common protocol (the Edmonton protocol). Methods We enrolled 36 subjects with type 1 diabetes mellitus, who underwent islet transplantation at nine international sites. Islets were prepared from pancreases of deceased donors and were transplanted within 2 hours after purification, without culture. The primary end point was defined as insulin independence with adequate glycemic control 1 year after the final transplantation. Results Of the 36 subjects, 16 (44%) met the primary end point, 10 (28%) had partial function, and 10 (28%) had complete graft loss 1 year after the final transplantation. A total of 21 subjects (58%) attained insulin independence with good glycemic control at any point throughout the trial. Of these subjects, 16 (76%) required insulin again at 2 years; 5 of the 16 subjects who reached the primary end point (31%) remained insulin-independent at 2 years. Conclusions Islet transplantation with the use of the Edmonton protocol can successfully restore long-term endogenous insulin production and glycemic stability in subjects with type 1 diabetes mellitus and unstable control, but insulin independence is usually not sustainable. Persistent islet function even without insulin independence provides both protection from severe hypoglycemia and improved levels of glycated hemoglobin. (ClinicalTrials.gov number, NCT00014911.)

Insights into social insects from the genome of the honeybee Apis mellifera

Abstract: Here we report the genome sequence of the honeybee Apis mellifera, a key model for social behaviour and essential to global ecology through pollination. Compared with other sequenced insect genomes, the A. mellifera genome has high A+T and CpG contents, lacks major transposon families, evolves more slowly, and is more similar to vertebrates for circadian rhythm, RNA interference and DNA methylation genes, among others. Furthermore, A. mellifera has fewer genes for innate immunity, detoxification enzymes, cuticle-forming proteins and gustatory receptors, more genes for odorant receptors, and novel genes for nectar and pollen utilization, consistent with its ecology and social organization. Compared to Drosophila, genes in early developmental pathways differ in Apis, whereas similarities exist for functions that differ markedly, such as sex determination, brain function and behaviour. Population genetics suggests a novel African origin for the species A. mellifera and insights into whether Africanized bees spread throughout the New World via hybridization or displacement.

Accurate photometric redshifts for the CFHT legacy survey calibrated using the VIMOS VLT deep survey

Abstract: We present photometric redshifts for an uniquely large and deep sample of 522286 objects with i'_{AB}<25 in the Canada-France Legacy Survey ``Deep Survey'' fields, which cover a total effective area of 3.2 deg^2. We use 3241 spectroscopic redshifts with 0

Calpain-mediated cleavage of Atg5 switches autophagy to apoptosis.

Abstract: Autophagy-related gene (Atg) 5 is a gene product required for the formation of autophagosomes. Here, we report that Atg5, in addition to the promotion of autophagy, enhances susceptibility towards apoptotic stimuli. Enforced expression of Atg5-sensitized tumour cells to anticancer drug treatment both in vitro and in vivo. In contrast, silencing the Atg5 gene with short interfering RNA (siRNA) resulted in partial resistance to chemotherapy. Apoptosis was associated with calpain-mediated Atg5 cleavage, resulting in an amino-terminal cleavage product with a relative molecular mass of 24,000 (Mr 24K). Atg5 cleavage was observed independent of the cell type and the apoptotic stimulus, suggesting that calpain activation and Atg5 cleavage are general phenomena in apoptotic cells. Truncated Atg5 translocated from the cytosol to mitochondria, associated with the anti-apoptotic molecule Bcl-xL and triggered cytochrome c release and caspase activation. Taken together, calpain-mediated Atg5 cleavage provokes apoptotic cell death, therefore, represents a molecular link between autophagy and apoptosis--a finding with potential importance for clinical anticancer therapies.

Interleukin-6 and chronic inflammation.

Abstract: Interleukin (IL)-6 is produced at the site of inflammation and plays a key role in the acute phase response as defined by a variety of clinical and biological features such as the production of acute phase proteins. IL-6 in combination with its soluble receptor sIL-6Rα, dictates the transition from acute to chonic inflammation by changing the nature of leucocyte infiltrate (from polymorphonuclear neutrophils to monocyte/macrophages). In addition, IL-6 exerts stimulatory effects on T- and B-cells, thus favoring chronic inflammatory responses. Strategies targeting IL-6 and IL-6 signaling led to effective prevention and treatment of models of rheumatoid arthritis and other chronic inflammatory diseases.

Estimating Trade Restrictiveness Indices

Abstract: The objective of this paper is to provide indicators of trade restrictiveness that include both measures of tariff and nontariff barriers for 91 developing and industrial countries. For each country, the authors estimate three trade restrictiveness indices. The first one summarizes the degree of trade distortions that each country imposes on itself through its own trade policies. The second one focuses on the trade distortions imposed by each country on its import bundle. The last index focuses on market access and summarizes the trade distortions imposed by the rest of the world on each country's export bundle. All indices are estimated for the broad aggregates of manufacturing and agriculture products. Results suggest that poor countries (and those with the highest poverty headcount) tend to be more restrictive, but they also face the highest trade barriers on their export bundle. This is partly explained by the fact that agriculture protection is generally larger than manufacturing protection. Nontariff barriers contribute more than 70 percent on average to world protection, underlying their importance for any study on trade protection.

Evidence-based model for hand transmission during patient care and the role of improved practices

Abstract: Hand cleansing is the primary action to reduce health-care-associated infection and cross-transmission of antimicrobial-resistant pathogens. Patient-to-patient transmission of pathogens via health-care workers' hands requires five sequential steps: (1) organisms are present on the patient's skin or have been shed onto fomites in the patient's immediate environment; (2) organisms must be transferred to health-care workers' hands; (3) organisms must be capable of surviving on health-care workers' hands for at least several minutes; (4) handwashing or hand antisepsis by the health-care worker must be inadequate or omitted entirely, or the agent used for hand hygiene inappropriate; and (5) the caregiver's contaminated hand(s) must come into direct contact with another patient or with a fomite in direct contact with the patient. We review the evidence supporting each of these steps and propose a dynamic model for hand hygiene research and education strategies, together with corresponding indications for hand hygiene during patient care.

Measurement of neutrino oscillation by the K2K experiment

Abstract: We present measurements of {nu}{sub {mu}} disappearance in K2K, the KEK to Kamioka long-baseline neutrino oscillation experiment. One-hundred and twelve beam-originated neutrino events are observed in the fiducial volume of Super-Kamiokande with an expectation of 158.1{sub -8.6}{sup +9.2} events without oscillation. A distortion of the energy spectrum is also seen in 58 single-ring muonlike events with reconstructed energies. The probability that the observations are explained by the expectation for no neutrino oscillation is 0.0015% (4.3{sigma}). In a two-flavor oscillation scenario, the allowed {delta}m{sup 2} region at sin{sup 2}2{theta}=1 is between 1.9 and 3.5x10{sup -3} eV{sup 2} at the 90% C.L. with a best-fit value of 2.8x10{sup -3} eV{sup 2}.

Nitric oxide-induced mitochondrial fission is regulated by dynamin-related GTPases in neurons.

Abstract: Mitochondria are present as tubular organelles in neuronal projections. Here, we report that mitochondria undergo profound fission in response to nitric oxide (NO) in cortical neurons of primary cultures. Mitochondrial fission by NO occurs long before neurite injury and neuronal cell death. Furthermore, fission is accompanied by ultrastructural damage of mitochondria, autophagy, ATP decline and generation of free radicals. Fission is occasionally asymmetric and can be reversible. Strikingly, mitochondrial fission is also an early event in ischemic stroke in vivo. Mitofusin 1 (Mfn1) or dominant-negative Dynamin related protein 1 (Drp1K38A) inhibits mitochondrial fission induced by NO, rotenone and Amyloid-β peptide. Conversely, overexpression of Drp1 or Fis1 elicits fission and increases neuronal loss. Importantly, NO-induced neuronal cell death was mitigated by Mfn1 and Drp1K38A. Thus, persistent mitochondrial fission may play a causal role in NO-mediated neurotoxicity.

From Bell's Theorem to Secure Quantum Key Distribution

Abstract: The first step in any quantum key distribution (QKD) protocol consists of sequences of measurements that produce correlated classical data. We show that these correlation data must violate some Bell inequality in order to contain distillable secrecy, if not they could be produced by quantum measurements performed on a separable state of larger dimension. We introduce a new QKD protocol and prove its security against any individual attack by an adversary only limited by the no-signaling condition.

GENCODE: producing a reference annotation for ENCODE

Abstract: Background The GENCODE consortium was formed to identify and map all protein-coding genes within the ENCODE regions. This was achieved by a combination of initial manual annotation by the HAVANA team, experimental validation by the GENCODE consortium and a refinement of the annotation based on these experimental results.

Contribution of the arbuscular mycorrhizal symbiosis to heavy metal phytoremediation.

Abstract: High concentrations of heavy metals (HM) in the soil have detrimental effects on ecosystems and are a risk to human health as they can enter the food chain via agricultural products or contaminated drinking water. Phytoremediation, a sustainable and inexpensive technology based on the removal of pollutants from the environment by plants, is becoming an increasingly important objective in plant research. However, as phytoremediation is a slow process, improvement of efficiency and thus increased stabilization or removal of HMs from soils is an important goal. Arbuscular mycorrhizal (AM) fungi provide an attractive system to advance plant-based environmental clean-up. During symbiotic interaction the hyphal network functionally extends the root system of their hosts. Thus, plants in symbiosis with AM fungi have the potential to take up HM from an enlarged soil volume. In this review, we summarize current knowledge about the contribution of the AM symbiosis to phytoremediation of heavy metals.

Chronic Palmitate But Not Oleate Exposure Induces Endoplasmic Reticulum Stress, Which May Contribute to INS-1 Pancreatic β-Cell Apoptosis

Abstract: Chronic free fatty acid (FFA) exposure induces pancreatic beta-cell death, which may contribute to the development of type 2 diabetes. The mechanisms involved in FFA-induced cell death are not completely understood. Here we have investigated the effect of FFA on endoplasmic reticulum (ER) stress pathways in INS-1 pancreatic beta-cells. INS-1 cells exposed to palmitate for 16-24 h under serum-free conditions showed marked apoptosis and increased protein levels of phosphorylated eukaryotic translation initiation factor 2alpha (eIF2alpha), activating transcription factor 4 (ATF4), X box-binding protein 1 (XBP-1), and C/EBP homologous transcription factor (CHOP) compared with control cells. The CHOP transcription factor has been implicated in mediating ER stress-induced apoptosis. Unexpectedly, the levels of the ER chaperone proteins Grp78/BiP and PDI were not affected by palmitate treatment, suggesting that the cell protective aspects of the unfolded protein response (UPR) are not up-regulated by palmitate. Palmitate-treated cells had markedly altered distribution of ER chaperones and altered ER morphology, suggesting that accumulation of misfolded proteins might trigger the ER stress response. In contrast, oleate treatment did not significantly induce the UPR pathways, nor was it as detrimental to INS-1 beta-cells. The results suggest that activation of the UPR may significantly contribute to palmitate- but not oleate-induced pancreatic beta-cell death.

Rhythmic CLOCK-BMAL1 binding to multiple E-box motifs drives circadian Dbp transcription and chromatin transitions.

Abstract: Mammalian circadian rhythms are based on transcriptional and post-translational feedback loops. Essentially, the activity of the transcription factors BMAL1 (also known as MOP3) and CLOCK is rhythmically counterbalanced by Period (PER) and Cryptochrome (CRY) proteins to govern time of day-dependent gene expression. Here we show that circadian regulation of the mouse albumin D element-binding protein (Dbp) gene involves rhythmic binding of BMAL1 and CLOCK and marked daily chromatin transitions. Thus, the Dbp transcription cycle is paralleled by binding of BMAL1 and CLOCK to multiple extra- and intragenic E boxes, acetylation of Lys9 of histone H3, trimethylation of Lys4 of histone H3 and a reduction of histone density. In contrast, the antiphasic daily repression cycle is accompanied by dimethylation of Lys9 of histone H3, the binding of heterochromatin protein 1alpha and an increase in histone density. The rhythmic conversion of transcriptionally permissive chromatin to facultative heterochromatin relies on the presence of functional BMAL1-CLOCK binding sites.

Search for neutral MSSM Higgs bosons at LEP

Abstract: The four LEP collaborations, ALEPH, DELPHI, L3 and OPAL, have searched for the neutral Higgs bosons which are predicted by the Minimal Supersymmetric standard model (MSSM). The data of the four collaborations are statistically combined and examined for their consistency with the background hypothesis and with a possible Higgs boson signal. The combined LEP data show no significant excess of events which would indicate the production of Higgs bosons. The search results are used to set upper bounds on the cross-sections of various Higgs-like event topologies. The results are interpreted within the MSSM in a number of “benchmark” models, including CP-conserving and CP-violating scenarios. These interpretations lead in all cases to large exclusions in the MSSM parameter space. Absolute limits are set on the parameter cosβ and, in some scenarios, on the masses of neutral Higgs bosons.

3D Lyα radiation transfer. I. Understanding Lyα line profile morphologies

Abstract: Aims. The development of a general code for 3D Lyα radiation transfer in galaxies to understand the diversity of Lya line profiles observed in star-forming galaxies and related objects. Methods. Using a Monte Carlo technique, we developed a 3D Lya radiation transfer code that allows for prescribed arbitrary hydrogen density, ionisation, temperature structures, dust distributions, arbitrary velocity fields, and UV photon sources. As a first test and application we examined the Lyα line profiles predicted for several simple geometrical configurations and their dependence on the main input parameters. Results. Overall, we find line profiles reaching from doubly peaked symmetric emission to symmetric Voigt (absorption) in static configurations with increasing dust content, and asymmetric red- (blue-) shifted emission lines with a blue (red) counterpart ranging from absorption to emission (with increasing line/continuum strength) in expanding (infalling) media. In particular we find the following results to be interesting for the interpretation of Lyα profiles from galaxies. 1) Standard Lya absorption line fitting of global spectra of galaxies may lead to an underestimation of the true hydrogen column density in certain geometrical conditions; 2) Normal (inverted) P-Cygni-like Lyα profiles can be obtained in expanding (infalling) media from objects without any intrinsic Lyα emission, as a natural consequence of radiation transfer effects; 3) The formation and the detailed shape of Lyα profiles resulting from expanding shells has been thoroughly revised. In particular we find that, for sufficiently large column densities (N H ≥ 10 20 cm -2 ), the position of the main Lya emission peak is quite generally redshifted by approximately twice the expansion velocity. This is in excellent agreement with the observations of z∼3 3 LBGs, which show that Lya is redshifted by ∼2V exp , where V exp is the expansion velocity measured from the interstellar absorption lines blueshifted with respect to the stellar redshift. This finding also indicates that large-scale, fairly symmetric shell structures must be a good description of the outflows in LBGs.

Role of frontal versus temporal cortex in verbal fluency as revealed by voxel-based lesion symptom mapping.

Abstract: Category and letter fluency tasks have been used to demonstrate psychological and neurological dissociations between semantic and phonological aspects of word retrieval. Some previous neuroimaging and lesion studies have suggested that category fluency (semantic-based word retrieval) is mediated primarily by temporal cortex, while letter fluency (letter-based word retrieval) is mediated primarily by frontal cortex. Other studies have suggested that both letter and category fluency are mediated by frontal cortex. We tested these hypotheses using voxel-based lesion symptom mapping (VLSM) in a group of 48 left-hemisphere stroke patients. VLSM maps revealed that category and letter fluency deficits correlate with lesions in temporal and frontal cortices, respectively. Other regions, including parietal cortex, were significantly implicated in both tasks. Our findings are therefore consistent with the hypothesis that temporal cortex subserves word retrieval constrained by semantics, whereas frontal regions are more critical for strategic word retrieval constrained by phonology. (JINS, 2006, 12, 896–900.)

Trojan-horse attacks on quantum-key-distribution systems

Abstract: General Trojan-horse attacks on quantum-key-distribution systems, i.e., attacks on Alice or Bob's system via the quantum channel, are analyzed. We illustrate the power of such attacks with today's technology and conclude that all systems must implement active counter measures. In particular, all systems must include an auxiliary detector that monitors any incoming light. We show that such counter measures can be efficient, provided that enough additional privacy amplification is applied to the data. We present a practical way to reduce the maximal information gain that an adversary can gain using Trojan-horse attacks. This does reduce the security analysis of the two-way plug-and-play implementation to those of the standard one-way systems.

New insights into myosin evolution and classification

Abstract: Myosins are eukaryotic actin-dependent molecular motors important for a broad range of functions like muscle contraction, vision, hearing, cell motility, and host cell invasion of apicomplexan parasites. Myosin heavy chains consist of distinct head, neck, and tail domains and have previously been categorized into 18 different classes based on phylogenetic analysis of their conserved heads. Here we describe a comprehensive phylogenetic examination of many previously unclassified myosins, with particular emphasis on sequences from apicomplexan and other chromalveolate protists including the model organism Toxoplasma, the malaria parasite Plasmodium, and the ciliate Tetrahymena. Using different phylogenetic inference methods and taking protein domain architectures, specific amino acid polymorphisms, and organismal distribution into account, we demonstrate a hitherto unrecognized common origin for ciliate and apicomplexan class XIV myosins. Our data also suggest common origins for some apicomplexan myosins and class VI, for classes II and XVIII, for classes XII and XV, and for some microsporidian myosins and class V, thereby reconciling evolutionary history and myosin structure in several cases and corroborating the common coevolution of myosin head, neck, and tail domains. Six novel myosin classes are established to accommodate sequences from chordate metazoans (class XIX), insects (class XX), kinetoplastids (class XXI), and apicomplexans and diatom algae (classes XXII, XXIII, and XXIV). These myosin (sub)classes include sequences with protein domains (FYVE, WW, UBA, ATS1-like, and WD40) previously unknown to be associated with myosin motors. Regarding the apicomplexan "myosome," we significantly update class XIV classification, propose a systematic naming convention, and discuss possible functions in these parasites.

Electrostatic modification of novel materials

Abstract: Application of the field-effect transistor principle to novel materials to achieve electrostatic doping is a relatively new research area. It may provide the opportunity to bring about modifications of the electronic and magnetic properties of materials through controlled and reversible changes of the carrier concentration without modifying the level of disorder, as occurs when chemical composition is altered. As well as providing a basis for new devices, electrostatic doping can in principle serve as a tool for studying quantum critical behavior, by permitting the ground state of a system to be tuned in a controlled fashion. In this paper progress in electrostatic doping of a number of materials systems is reviewed. These include structures containing complex oxides, such as cuprate superconductors and colossal magnetoresistive compounds, organic semiconductors, in the form of both single crystals and thin films, inorganic layered compounds, single molecules, and magnetic semiconductors. Recent progress in the field is discussed, including enabling experiments and technologies, open scientific issues and challenges, and future research opportunities. For many of the materials considered, some of the results can be anticipated by combining knowledge of macroscopic or bulk properties and the understanding of the field-effect configuration developed during the course of the evolution of conventional microelectronics. However, because electrostatic doping is an interfacial phenomenon, which is largely an unexplored field, real progress will depend on the development of a better understanding of lattice distortion and charge transfer at interfaces in these systems.

The euro's trade effects

Abstract: This paper reviews and reassesses the methodology and principal findings of the "Rose effect," i.e., the trade effects of currency union, looking at both EMU and non-EMU currency unions. The consensus estimate suggests that the euro has already boosted intra-euro area trade by five to ten percent. The paper discusses a gamut of models that might explain the Rose effect in Europe and suggests a series of empirical test that could help identify the economic mechanisms involved.

The early star generations: the dominant effect of rotation on the cno yields

Abstract: Context. Aims. We examine the role of rotation on the evolution and chemical yields of very metal-poor stars. Methods. The models include the same physics, which was applied successfully at the solar Z and for the SMC, in particular, shear diffusion, meridional circulation, horizontal turbulence, and rotationally enhanced mass loss. Results. Models of very low Z experience a much stronger internal mixing in all phases than at solar Z . Also, rotating models at very low Z , contrary to the usual considerations, show a large mass loss, which mainly results from the efficient mixing of the products of the 3α reaction into the H-burning shell. This mixing allows convective dredge-up to enrich the stellar surface in heavy elements during the red supergiant phase, which in turn favours a large loss of mass by stellar winds, especially as rotation also increases the duration of this phase. On the whole, the low Z stars may lose about half of their mass. Massive stars initially rotating at half of their critical velocity are likely to avoid the pair-instability supernova. The chemical composition of the rotationally enhanced winds of very low Z stars show large CNO enhancements by factors of 103 to 107 , together with large excesses of 13 C and 17 O and moderate amounts of Na and Al. The excesses of primary N are particularly striking. When these ejecta from the rotationally enhanced winds are diluted with the supernova ejecta from the corresponding CO cores, we find [C/Fe], [N/Fe], [O/Fe] abundance ratios that are very similar to those observed in the C-rich, extremely metal-poor stars (CEMP). We show that rotating AGB stars and rotating massive stars have about the same effects on the CNO enhancements. Abundances of s-process elements and the 12 C/13 C ratio could help us to distinguish between contributions from AGB and massive stars. Conclusions.