Showing papers by "McGill University published in 2008"

Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight?

Abstract: MicroRNAs constitute a large family of small, approximately 21-nucleotide-long, non-coding RNAs that have emerged as key post-transcriptional regulators of gene expression in metazoans and plants. In mammals, microRNAs are predicted to control the activity of approximately 30% of all protein-coding genes, and have been shown to participate in the regulation of almost every cellular process investigated so far. By base pairing to mRNAs, microRNAs mediate translational repression or mRNA degradation. This Review summarizes the current understanding of the mechanistic aspects of microRNA-induced repression of translation and discusses some of the controversies regarding different modes of microRNA function.

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Abstract: Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

Insulin and insulin-like growth factor signalling in neoplasia

Abstract: Insulin and insulin-like growth factors (IGFs) are well known as key regulators of energy metabolism and growth. There is now considerable evidence that these hormones and the signal transduction networks they regulate have important roles in neoplasia. Epidermiological, clinical and laboratory research methods are being used to investigate novel cancer prevention and treatment strategies related to insulin and IGF signalling. Pharmacological strategies under study include the use of novel receptor-specific antibodies, receptor kinase inhibitors and AMP-activated protein kinase activators such as metformin. There is evidence that insulin and IGF signalling may also be relevant to dietary and lifestyle factors that influence cancer risk and cancer prognosis. Recent results are encouraging and have justified the expansion of many translational research programmes.

Farming the planet: 1. Geographic distribution of global agricultural lands in the year 2000

Abstract: million km 2 of cropland (12% of the Earth’s ice-free land surface) and 28.0 (90% confidence range of 23.6–30.0) million km 2 of pasture (22%) in the year 2000.

Stromal gene expression predicts clinical outcome in breast cancer

Abstract: Although it is increasingly evident that cancer is influenced by signals emanating from tumor stroma, little is known regarding how changes in stromal gene expression affect epithelial tumor progression. We used laser capture microdissection to compare gene expression profiles of tumor stroma from 53 primary breast tumors and derived signatures strongly associated with clinical outcome. We present a new stroma-derived prognostic predictor (SDPP) that stratifies disease outcome independently of standard clinical prognostic factors and published expression-based predictors. The SDPP predicts outcome in several published whole tumor-derived expression data sets, identifies poor-outcome individuals from multiple clinical subtypes, including lymph node-negative tumors, and shows increased accuracy with respect to previously published predictors, especially for HER2-positive tumors. Prognostic power increases substantially when the predictor is combined with existing outcome predictors. Genes represented in the SDPP reveal the strong prognostic capacity of differential immune responses as well as angiogenic and hypoxic responses, highlighting the importance of stromal biology in tumor progression.

Auditory Scene Analysis

Abstract: Auditory scene analysis (ASA) is defined and the problem of partitioning the time-varying spectrum resulting from mixtures of individual acoustic signals is described Some basic facts about ASA are presented These include causes and effects of auditory organization (sequential, simultaneous, and the old-plus-new heuristic) Processes employing different cues collaborate and compete in determining the final organization of the mixture These processes take advantage of regularities in the mixture that give clues about how to parse it There are general regularities that apply to most types of sound, as well as regularities in particular types of sound The general ones are hypothesized to be used by innate processes, and the ones specific to restricted environments to be used by learned processes in humans and possibly by innate ones in animals The use of brain recordings and the study of nonhuman animals is discussed

Farming the planet: 2. Geographic distribution of crop areas, yields, physiological types, and net primary production in the year 2000

Abstract: [1] Croplands cover ∼15 million km2 of the planet and provide the bulk of the food and fiber essential to human well-being. Most global land cover data sets from satellites group croplands into just a few categories, thereby excluding information that is critical for answering key questions ranging from biodiversity conservation to food security to biogeochemical cycling. Information about agricultural land use practices like crop selection, yield, and fertilizer use is even more limited. Here we present land use data sets created by combining national, state, and county level census statistics with a recently updated global data set of croplands on a 5 min by 5 min (∼10 km by 10 km) latitude-longitude grid. The resulting land use data sets depict circa the year 2000 the area (harvested) and yield of 175 distinct crops of the world. We aggregate these individual crop maps to produce novel maps of 11 major crop groups, crop net primary production, and four physiologically based crop types: annuals/perennials, herbaceous/shrubs/trees, C3/C4, and leguminous/nonleguminous.

New Global Hydrography Derived From Spaceborne Elevation Data

Abstract: To study the Earth system and to better understand the implications of global environmental change, there is a growing need for large-scale hydrographic data sets that serve as prerequisites in a variety of analyses and applications, ranging from regional watershed and freshwater conservation planning to global hydrological, climate, biogeochemical, and land surface modeling. Yet while countless hydrographic maps exist for well-known river basins and individual nations, there is a lack of seamless high-quality data on large scales such as continents or the entire globe. Data for many large international basins are patchy, and remote areas are often poorly mapped. In response to these limitations, a team of scientists has developed data and created maps of the world's rivers that provide the research community with more reliable information about where streams and watersheds occur on the Earth's surface and how water drains the landscape. The new product, known as HydroSHEDS (Hydrological Data and Maps Based on Shuttle Elevation Derivatives at Multiple Scales), provides this information at a resolution and quality unachieved by previous global data sets, such as HYDRO1k [U.S. Geological Survey (USGS), 2000].

Putting people in the map: anthropogenic biomes of the world

Abstract: Humans have fundamentally altered global patterns of biodiversity and ecosystem processes. Surprisingly, existing systems for representing these global patterns, including biome classifications, either ignore humans altogether or simplify human influence into, at most, four categories. Here, we present the first characterization of terrestrial biomes based on global patterns of sustained, direct human interaction with ecosystems. Eighteen “anthropogenic biomes” were identified through empirical analysis of global population, land use, and land cover. More than 75% of Earth's ice-free land showed evidence of alteration as a result of human residence and land use, with less than a quarter remaining as wildlands, supporting just 11% of terrestrial net primary production. Anthropogenic biomes offer a new way forward by acknowledging human influence on global ecosystems and moving us toward models and investigations of the terrestrial biosphere that integrate human and ecological systems.

Immortal Time Bias in Pharmacoepidemiology

Abstract: Immortal time is a span of cohort follow-up during which, because of exposure definition, the outcome under study could not occur. Bias from immortal time was first identified in the 1970s in epidemiology in the context of cohort studies of the survival benefit of heart transplantation. It recently resurfaced in pharmaco-epidemiology, with several observational studies reporting that various medications can be extremely effective at reducing morbidity and mortality. These studies, while using different cohort designs, all involved some form of immortal time and the corresponding bias. In this paper, the author describes various cohort study designs leading to this bias, quantifies its magnitude under different survival distributions, and illustrates it by using data from a cohort of lung cancer patients. The author shows that for time-based, event-based, and exposure-based cohort definitions, the bias in the rate ratio resulting from misclassified or excluded immortal time increases proportionately to the duration of immortal time. The bias is more pronounced with a decreasing hazard function for the outcome event, as illustrated with the Weibull distribution compared with a constant hazard from the exponential distribution. In conclusion, observational studies of drug benefit in which computerized databases are used must be designed and analyzed properly to avoid immortal time bias.

The Rpd3/Hda1 family of lysine deacetylases: from bacteria and yeast to mice and men.

Abstract: The Rpd3/Hda1 family of protein lysine deacetylases has numerous substrates and diverse functions. Whereas class I enzymes are multiprotein histone deacetylase complexes that are crucial for chromatin modification and transcriptional regulation, some class II enzymes function as signal transducers that are regulated by nucleocytoplasmic translocation. Protein lysine deacetylases have a pivotal role in numerous biological processes and can be divided into the Rpd3/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3/Hda1 family contains 11 members, traditionally referred to as histone deacetylases (HDAC) 1–11, which are further grouped into classes I, II and IV. Whereas most class I HDACs are subunits of multiprotein nuclear complexes that are crucial for transcriptional repression and epigenetic landscaping, class II members regulate cytoplasmic processes or function as signal transducers that shuttle between the cytoplasm and the nucleus. Little is known about class IV HDAC11, although its evolutionary conservation implies a fundamental role in various organisms.

Reducing bias through directed acyclic graphs.

Abstract: Background The objective of most biomedical research is to determine an unbiased estimate of effect for an exposure on an outcome, i.e. to make causal inferences about the exposure. Recent developments in epidemiology have shown that traditional methods of identifying confounding and adjusting for confounding may be inadequate.

Usefulness of the Berg Balance Scale in Stroke Rehabilitation: A Systematic Review

Abstract: Background. In a recent study of 655 physical therapists working with a stroke population, the Berg Balance Scale (BBS) was identified as the most commonly used assessment tool across the continuum of stroke rehabilitation. Given the widespread popularity of the BBS, it is important to critically appraise the BBS for its use with a stroke population. Objective. The purposes of this study were to conduct a systematic review of the psychometric properties of the BBS specific to stroke and to identify strengths and weaknesses in its usefulness for stroke rehabilitation. Results. Twenty-one studies examining the psychometric properties of the BBS with a stroke population were retrieved. Internal consistency was excellent (Cronbach alpha.92‐.98) as was interrater reliability (intraclass correlation coefficients [ICCs].95‐.98), intrarater reliability (ICC.97), and test-retest reliability (ICC.98). Sixteen studies focused on validity and generally found excellent correlations with the Barthel Index, the Postural Assessment Scale for Stroke Patients, Functional Reach Test, the balance subscale of Fugl-Meyer Assessment, the Functional Independence Measure, the Rivermead Mobility Index (except for weight shift and step-up items), and gait speed. Berg Balance Scale scores predicted length of stay, discharge destination, motor ability at 180 days poststroke, and disability level at 90 days, but these scores were not predictive of falls. Eight studies focused on responsiveness; all reported moderate to excellent sensitivity. Three studies found floor or ceiling effects. Discussion and Conclusion. The BBS is a psychometrically sound measure of balance impairment for use in poststroke assessment. Given the floor and ceiling effects, clinicians may want to use the BBS in conjunction with other balance measures.

The Keck Planet Search: Detectability and the Minimum Mass and Orbital Period Distribution of Extrasolar Planets

Abstract: . We analyze 8 years of precise radial velocity measurements from the Keck Planet Search, characterizing the detection threshold, selection effects, and completeness of the survey. We first carry out a systematic search for planets, by assessing the false-alarm probability associated with Keplerian orbit fits to the data. This allows us to understand the detection threshold for each star in terms of the number and time baseline of the observations, and the underlying “noise” from measurement errors, intrinsic stellar jitter, or additional low-mass planets. We show that all planets with orbital periods P 20 m s-1 K > 20 m s - 1 , and eccentricities e ≲ 0.6 e ≲ 0.6 have been announced, and we summarize the candidates at lower amplitudes and longer orbital periods. For the remaining stars, we calculate upper limits on the velocity amplitude of a companion. For orbital periods less than the duration of the observations, these are typically ...

Breastfeeding and Child Cognitive Development: New Evidence From a Large Randomized Trial

Abstract: Context: The evidence that breastfeeding improves cognitive development is based almost entirely on observational studies and is thus prone to confounding by subtle behavioral differences in the breastfeeding mother’s behavior or her interaction with the infant. Objective: To assess whether prolonged and exclusive breastfeeding improves children’s cognitive ability at age 6.5 years.

Photomobile polymer materials: towards light-driven plastic motors.

Abstract: As light is a good energy source that can be controlled remotely, instantly, and precisely, light-driven soft actuators could play an important role for novel applications in wideranging industrial and medical fields. Liquid-crystalline elastomers (LCEs) are unique materials having both properties of liquid crystals (LCs) and elastomers, and a large deformation can be generated in LCEs, such as reversible contraction and expansion, and even bending, by incorporating photochromic molecules, such as an azobenzene, with the aid of photochemical reactions of these chromophores. Herein we demonstrate new sophisticated motions of LCEs and their composite materials: a plastic motor driven only by light. If materials absorb light and change their shape or volume, they can convert light energy directly into mechanical work (the photomechanical effect) and could be very efficient as a single-step energy conversion. Furthermore, these photomobile materials would be widely applicable because they can be controlled remotely just by manipulating the irradiation conditions. LCEs show an anisotropic order of mesogens with a cooperative effect, which leads them to undergo an anisotropic contraction along the alignment direction of mesogens when heated above their LC-isotropic(I) phase transition temperatures (TLC-I) and an expansion by lowering the temperature below TLC-I. [1, 13–18] The expansion and contraction is due to the microscopic change in alignment of mesogens, followed by the significant macroscopic change in order through the cooperative movement of mesogens and polymer segments. It is well known that when azobenzene derivatives are incorporated into LCs, the LC-I phase transition can be induced isothermally by irradiation with UV light to cause trans–cis photoisomerization, and the I-LC reverse-phase transition by irradiation with visible light to cause cis–trans back-isomerization. This photoinduced phase transition (or photoinduced reduction of LC order) has led successfully to a reversible deformation of LCEs containing azobenzene chromophores just by changing the wavelength of actinic light. Although the photoinduced deformation of LCEs previously reported is large and interesting, it is limited to contraction/expansion and bending, preventing them from being used for actual applications. Herein we report potentially applicable rotational motions of azobenzene-containing LCEs and their composite materials, including a first lightdriven plastic motor with laminated films composed of an LCE film and a flexible polyethylene (PE) sheet. The LCE films were prepared by photopolymerization of a mixture of an LC monomer containing an azobenzene moiety (molecule 1 shown in Scheme 1) and an LC diacrylate with an azobenzene moiety (2 in Scheme 1) with a ratio of 20/ 80 mol/mol, containing 2 mol% of a photoinitiator in a glass cell coated with rubbed polyimide alignment layers. The photopolymerization was conducted at a temperature at which the mixture exhibited a smectic phase. The glasstransition temperature of the LCE films is at about room temperature, allowing the LCE films to work at room temperature in air, as the films are flexible enough at this temperature. We prepared a continuous ring of the LCE film by connecting both ends of the film. The azobenzene mesogens were aligned along the circular direction of the ring. Upon exposure to UV light from the downside right and visible light from the upside right simultaneously (Figure 1), the ring

Combining individual interviews and focus groups to enhance data richness

Abstract: Title. Combining individual interviews and focus groups to enhance data richness. Aim. This paper is a presentation of the critical reflection on the types of findings obtained from the combination of individual interviews and focus groups, and how such triangulation contributes to knowledge production and synthesis. Background. Increasingly, qualitative method triangulation is advocated as a strategy to achieve more comprehensive understandings of phenomena. Although ontological and epistemological issues pertaining to triangulation are a topic of debate, more practical discussions are needed on its potential contributions, such as enhanced data richness and depth of inquiry. Method. Data gathered through individual interviews and focus groups from a study on patterns of cancer information-seeking behaviour are used to exemplify the added-value but also the challenges of relying on methods combination. Findings. The integration of focus group and individual interview data made three main contributions: a productive iterative process whereby an initial model of the phenomenon guided the exploration of individual accounts and successive individual data further enriched the conceptualisation of the phenomenon; identification of the individual and contextual circumstances surrounding the phenomenon, which added to the interpretation of the structure of the phenomenon; and convergence of the central characteristics of the phenomenon across focus groups and individual interviews, which enhanced trustworthiness of findings. Conclusion. Although the use of triangulation is promising, more work is needed to identify the added-value or various outcomes pertaining to method combination and data integration.

Assembling Materials with DNA as the Guide

Abstract: DNA's remarkable molecular recognition properties and structural features make it one of the most promising templates to pattern materials with nanoscale precision. The emerging field of DNA nanotechnology strips this molecule from any preconceived biological role and exploits its simple code to generate addressable nanostructures in one, two, and three dimensions. These structures have been used to precisely position proteins, nanoparticles, transition metals, and other functional components into deliberately designed patterns. They can also act as templates for the growth of nanowires, aid in the structural determination of proteins, and provide new platforms for genomics applications. The field of DNA nanotechnology is growing in a number of directions, carrying with it the promise to substantially affect materials science and biology.

Peatlands and the carbon cycle: from local processes to global implications - a synthesis

Abstract: Although peatlands cover only 3% of the Earth's land surface, boreal and subarctic peatlands store about 15?30% of the world's soil carbon as peat. Despite their potential for large positive feedbacks to the climate system through sequestration and emission of greenhouse gases, peatlands are not explicitly included in global climate models and therefore in predictions of future climate change. In April 2007 a symposium was held in Wageningen, the Netherlands, to advance our understanding of peatland C cycling through integration across disciplines and research approaches and to develop a more synthetic picture of the present and future role of peatlands in the global C cycle and their interactions with the climate system. This paper aims to synthesize the main findings of the symposium, focusing on (i) small-scale processes, (ii) C fluxes at the landscape scale, and (iii) peatlands and climate. The paper concludes with a summary of the main drivers of the C balance of peatlands, and proposes directions for new research to reduce key uncertainties in our knowledge of C cycling in peatlands in order to facilitate the explicit inclusion of these ecosystems in a new generation of earth system models.

Analytical distributions for stochastic gene expression

Abstract: Gene expression is significantly stochastic making modeling of genetic networks challenging. We present an approximation that allows the calculation of not only the mean and variance, but also the distribution of protein numbers. We assume that proteins decay substantially more slowly than their mRNA and confirm that many genes satisfy this relation by using high-throughput data from budding yeast. For a two-stage model of gene expression, with transcription and translation as first-order reactions, we calculate the protein distribution for all times greater than several mRNA lifetimes and thus qualitatively predict the distribution of times for protein levels to first cross an arbitrary threshold. If in addition the fluctuates between inactive and active states, we can find the steady-state protein distribution, which can be bimodal if fluctuations of the promoter are slow. We show that our assumptions imply that protein synthesis occurs in geometrically distributed bursts and allows mRNA to be eliminated from a master equation description. In general, we find that protein distributions are asymmetric and may be poorly characterized by their mean and variance. Through maximum likelihood methods, our expressions should therefore allow more quantitative comparisons with experimental data. More generally, we introduce a technique to derive a simpler, effective dynamics for a stochastic system by eliminating a fast variable.

Fission-fusion dynamics: new research frameworks

Abstract: Renewed interest in fission‐fusion dynamics is due to the recognition that such dynamics may create unique challenges for social interaction and distinctive selective pressures acting on underlying communicative and cognitive abilities. New frameworks for integrating current knowledge on fission‐fusion dynamics emerge from a fundamental rethinking of the term “fission‐fusion” away from its current general use as a label for a particular modal type of social system (i.e., “fission‐fusion societies”). Specifically, because the degree of spatial and temporal cohesion of group members varies both within and across taxa, any social system can be described in terms of the extent to which it expresses fission‐fusion dynamics. This perspective has implications for socioecology, communication, cognitive demands, and human social evolution.

Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

Abstract: Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk.

An in Vivo Map of the Yeast Protein Interactome

Abstract: Protein interactions regulate the systems-level behavior of cells; thus, deciphering the structure and dynamics of protein interaction networks in their cellular context is a central goal in biology. We have performed a genome-wide in vivo screen for protein-protein interactions in Saccharomyces cerevisiae by means of a protein-fragment complementation assay (PCA). We identified 2770 interactions among 1124 endogenously expressed proteins. Comparison with previous studies confirmed known interactions, but most were not known, revealing a previously unexplored subspace of the yeast protein interactome. The PCA detected structural and topological relationships between proteins, providing an 8-nanometer-resolution map of dynamically interacting complexes in vivo and extended networks that provide insights into fundamental cellular processes, including cell polarization and autophagy, pathways that are evolutionarily conserved and central to both development and human health.

Vestibular System: The Many Facets of a Multimodal Sense

Abstract: Elegant sensory structures in the inner ear have evolved to measure head motion. These vestibular receptors consist of highly conserved semicircular canals and otolith organs. Unlike other senses, vestibular information in the central nervous system becomes immediately multisensory and multimodal. There is no overt, readily recognizable conscious sensation from these organs, yet vestibular signals contribute to a surprising range of brain functions, from the most automatic reflexes to spatial perception and motor coordination. Critical to these diverse, multimodal functions are multiple computationally intriguing levels of processing. For example, the need for multisensory integration necessitates vestibular representations in multiple reference frames. Proprioceptive-vestibular interactions, coupled with corollary discharge of a motor plan, allow the brain to distinguish actively generated from passive head movements. Finally, nonlinear interactions between otolith and canal signals allow the vestibular system to function as an inertial sensor and contribute critically to both navigation and spatial orientation.