Showing papers by "University of Southern California published in 2009"

Common polygenic variation contributes to risk of schizophrenia and bipolar disorder

Abstract: Schizophrenia is a severe mental disorder with a lifetime risk of about 1%, characterized by hallucinations, delusions and cognitive deficits, with heritability estimated at up to 80%(1,2). We performed a genome-wide association study of 3,322 European individuals with schizophrenia and 3,587 controls. Here we show, using two analytic approaches, the extent to which common genetic variation underlies the risk of schizophrenia. First, we implicate the major histocompatibility complex. Second, we provide molecular genetic evidence for a substantial polygenic component to the risk of schizophrenia involving thousands of common alleles of very small effect. We show that this component also contributes to the risk of bipolar disorder, but not to several non-psychiatric diseases.

The B73 Maize Genome: Complexity, Diversity, and Dynamics

Abstract: We report an improved draft nucleotide sequence of the 2.3-gigabase genome of maize, an important crop plant and model for biological research. Over 32,000 genes were predicted, of which 99.8% were placed on reference chromosomes. Nearly 85% of the genome is composed of hundreds of families of transposable elements, dispersed nonuniformly across the genome. These were responsible for the capture and amplification of numerous gene fragments and affect the composition, sizes, and positions of centromeres. We also report on the correlation of methylation-poor regions with Mu transposon insertions and recombination, and copy number variants with insertions and/or deletions, as well as how uneven gene losses between duplicated regions were involved in returning an ancient allotetraploid to a genetically diploid state. These analyses inform and set the stage for further investigations to improve our understanding of the domestication and agricultural improvements of maize.

Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

Abstract: Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.

Mesenchymal Stem Cells Derived from Dental Tissues vs. Those from Other Sources: Their Biology and Role in Regenerative Medicine

Abstract: To date, 5 different human dental stem/progenitor cells have been isolated and characterized: dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SHED), periodontal ligament stem cells (PDLSCs), stem cells from apical papilla (SCAP), and dental follicle progenitor cells (DFPCs). These post-natal populations have mesenchymal-stem-cell-like (MSC) qualities, including the capacity for self-renewal and multilineage differentiation potential. MSCs derived from bone marrow (BMMSCs) are capable of giving rise to various lineages of cells, such as osteogenic, chondrogenic, adipogenic, myogenic, and neurogenic cells. The dental-tissue-derived stem cells are isolated from specialized tissue with potent capacities to differentiate into odontogenic cells. However, they also have the ability to give rise to other cell lineages similar to, but different in potency from, that of BMMSCs. This article will review the isolation and characterization of the properties of different dental MSC-like populations in comparison with those of other MSCs, such as BMMSCs. Important issues in stem cell biology, such as stem cell niche, homing, and immunoregulation, will also be discussed.

Transfer Learning for Reinforcement Learning Domains: A Survey

Abstract: The reinforcement learning paradigm is a popular way to address problems that have only limited environmental feedback, rather than correctly labeled examples, as is common in other machine learning contexts. While significant progress has been made to improve learning in a single task, the idea of transfer learning has only recently been applied to reinforcement learning tasks. The core idea of transfer is that experience gained in learning to perform one task can help improve learning performance in a related, but different, task. In this article we present a framework that classifies transfer learning methods in terms of their capabilities and goals, and then use it to survey the existing literature, as well as to suggest future directions for transfer learning work.

Collection tree protocol

Abstract: This paper presents and evaluates two principles for wireless routing protocols. The first is datapath validation: data traffic quickly discovers and fixes routing inconsistencies. The second is adaptive beaconing: extending the Trickle algorithm to routing control traffic reduces route repair latency and sends fewer beacons.We evaluate datapath validation and adaptive beaconing in CTP Noe, a sensor network tree collection protocol. We use 12 different testbeds ranging in size from 20--310 nodes, comprising seven platforms, and six different link layers, on both interference-free and interference-prone channels. In all cases, CTP Noe delivers > 90% of packets. Many experiments achieve 99.9%. Compared to standard beaconing, CTP Noe sends 73% fewer beacons while reducing topology repair latency by 99.8%. Finally, when using low-power link layers, CTP Noe has duty cycles of 3% while supporting aggregate loads of 30 packets/minute.

Latent Variable Modeling of Differences and Changes with Longitudinal Data

Abstract: This review considers a common question in data analysis: What is the most useful way to analyze longitudinal repeated measures data? We discuss some contemporary forms of structural equation models (SEMs) based on the inclusion of latent variables. The specific goals of this review are to clarify basic SEM definitions, consider relations to classical models, focus on testable features of the new models, and provide recent references to more complete presentations. A broader goal is to illustrate why so many researchers are enthusiastic about the SEM approach to data analysis. We first outline some classic problems in longitudinal data analysis, consider definitions of differences and changes, and raise issues about measurement errors. We then present several classic SEMs based on the inclusion of invariant common factors and explain why these are so important. This leads to newer SEMs based on latent change scores, and we explain why these are useful.

Common variants at 30 loci contribute to polygenic dyslipidemia.

Abstract: Blood low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglyceride levels are risk factors for cardiovascular disease. To dissect the polygenic basis of these traits, we conducted genome-wide association screens in 19,840 individuals and replication in up to 20,623 individuals. We identified 30 distinct loci associated with lipoprotein concentrations (each with P < 5 x 10(-8)), including 11 loci that reached genome-wide significance for the first time. The 11 newly defined loci include common variants associated with LDL cholesterol near ABCG8, MAFB, HNF1A and TIMD4; with HDL cholesterol near ANGPTL4, FADS1-FADS2-FADS3, HNF4A, LCAT, PLTP and TTC39B; and with triglycerides near AMAC1L2, FADS1-FADS2-FADS3 and PLTP. The proportion of individuals exceeding clinical cut points for high LDL cholesterol, low HDL cholesterol and high triglycerides varied according to an allelic dosage score (P < 10(-15) for each trend). These results suggest that the cumulative effect of multiple common variants contributes to polygenic dyslipidemia.

Chemical recycling of carbon dioxide to methanol and dimethyl ether: from greenhouse gas to renewable, environmentally carbon neutral fuels and synthetic hydrocarbons.

Abstract: Nature’s photosynthesis uses the sun’s energy with chlorophyll in plants as a catalyst to recycle carbon dioxide and water into new plant life. Only given sufficient geological time can new fossil fuels be formed naturally. In contrast, chemical recycling of carbon dioxide from natural and industrial sources as well as varied human activities or even from the air itself to methanol or dimethyl ether (DME) and their varied products can be achieved via its capture and subsequent reductive hydrogenative conversion. The present Perspective reviews this new approach and our research in the field over the last 15 years. Carbon recycling represents a significant aspect of our proposed Methanol Economy. Any available energy source (alternative energies such as solar, wind, geothermal, and atomic energy) can be used for the production of needed hydrogen and chemical conversion of CO2. Improved new methods for the efficient reductive conversion of CO2 to methanol and/or DME that we have developed include bireformin...

Covalent polymer functionalization of graphene nanosheets and mechanical properties of composites

Abstract: For developing high performance graphene-based nanocomposites, dispersal of graphene nanosheets in polymer hosts and precise interface control are challenging due to their strong interlayer cohesive energy and surface inertia. Here we report an efficient method to functionalize graphene nanosheets. The initiator molecules were covalently bonded to the graphene surface via a diazonium addition and the succeeding atom transfer radical polymerization linked polystyrene chains (82 wt% grafting efficiency) to the graphene nanosheets. The prominent confinement effect arising from nanosheets resulted in a 15 °C increase in the glass transition temperature of polystyrene compared to the pure polymer. The resulting polystyrene nanocomposites with 0.9 wt% graphene nanosheets revealed around 70% and 57% increases in tensile strength and Young's modulus. The protocol is believed to offer possibilities for optimizing the processing properties and interface structure of graphene-polymer nanocomposites.

Genome-wide association study identifies eight loci associated with blood pressure

Abstract: Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N ≤ 71,225 European ancestry, N ≤ 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N = 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 × 10(-24)), CYP1A2 (P = 1 × 10(-23)), FGF5 (P = 1 × 10(-21)), SH2B3 (P = 3 × 10(-18)), MTHFR (P = 2 × 10(-13)), c10orf107 (P = 1 × 10(-9)), ZNF652 (P = 5 × 10(-9)) and PLCD3 (P = 1 × 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

Sleep-disordered breathing and mortality: A prospective cohort study

Abstract: Background: Sleep-disordered breathing is a common condition associated with adverse health outcomes including hypertension and cardiovascular disease. The overall objective of this study was to determine whether sleep-disordered breathing and its sequelae of intermittent hypoxemia and recurrent arousals are associated with mortality in a community sample of adults aged 40 years or older. Methods and Findings: We prospectively examined whether sleep-disordered breathing was associated with an increased risk of death from any cause in 6,441 men and women participating in the Sleep Heart Health Study. Sleep-disordered breathing was assessed with the apnea–hypopnea index (AHI) based on an in-home polysomnogram. Survival analysis and proportional hazards regression models were used to calculate hazard ratios for mortality after adjusting for age, sex, race, smoking status, body mass index, and prevalent medical conditions. The average follow-up period for the cohort was 8.2 y during which 1,047 participants (587 men and 460 women) died. Compared to those without sleep-disordered breathing (AHI: ,5 events/h), the fully adjusted hazard ratios for all-cause mortality in those with mild (AHI: 5.0–14.9 events/h), moderate (AHI: 15.0–29.9 events/h), and severe (AHI: $30.0 events/h) sleep-disordered breathing were 0.93 (95% CI: 0.80– 1.08), 1.17 (95% CI: 0.97–1.42), and 1.46 (95% CI: 1.14–1.86), respectively. Stratified analyses by sex and age showed that the increased risk of death associated with severe sleep-disordered breathing was statistically significant in men aged 40–70 y (hazard ratio: 2.09; 95% CI: 1.31–3.33). Measures of sleep-related intermittent hypoxemia, but not sleep fragmentation, were independently associated with all-cause mortality. Coronary artery disease–related mortality associated with sleepdisordered breathing showed a pattern of association similar to all-cause mortality. Conclusions: Sleep-disordered breathing is associated with all-cause mortality and specifically that due to coronary artery disease, particularly in men aged 40–70 y with severe sleep-disordered breathing. Please see later in the article for the Editors’ Summary.

The genetics of quantitative traits: challenges and prospects.

Abstract: A major challenge in current biology is to understand the genetic basis of variation for quantitative traits. We review the principles of quantitative trait locus mapping and summarize insights about the genetic architecture of quantitative traits that have been obtained over the past decades. We are currently in the midst of a genomic revolution, which enables us to incorporate genetic variation in transcript abundance and other intermediate molecular phenotypes into a quantitative trait locus mapping framework. This systems genetics approach enables us to understand the biology inside the 'black box' that lies between genotype and phenotype in terms of causal networks of interacting genes.

Costly External Finance, Corporate Investment, and the Subprime Mortgage Credit Crisis

Abstract: We study the effect of the recent financial crisis on corporate investment. The crisis represents an unexplored negative shock to the supply of external finance for non-financial firms. Corporate investment declines significantly following the onset of the crisis, controlling for firm fixed effects and time-varying measures of investment opportunities. Consistent with a causal effect of a supply shock, the decline is greatest for firms that have low cash reserves or high net short-term debt, are financially constrained, or operate in industries dependent on external finance. To address endogeneity concerns, we measure firms’ financial positions as much as four years prior to the crisis, and confirm that similar results do not follow placebo crises in the summers of 2003–2006. Nor do similar results follow the negative demand shock caused by September 11, 2001. The effects weaken considerably beginning in the third quarter of 2008, when the demand-side effects of the crisis became apparent. Additional analysis suggests an important precautionary savings motive for seemingly excess cash that is generally overlooked in the literature.

Microbial community structure and its functional implications

Abstract: Marine microbial communities are engines of globally important processes, such as the marine carbon, nitrogen and sulphur cycles. Recent data on the structures of these communities show that they adhere to universal biological rules. Co-occurrence patterns can help define species identities, and systems-biology tools are revealing networks of interacting microorganisms. Some microbial systems are found to change predictably, helping us to anticipate how microbial communities and their activities will shift in a changing world.

Common genetic variants on 5p14.1 associate with autism spectrum disorders

Abstract: Several lines of evidence point to genetic involvement in autism spectrum disorders (ASDs), neurodevelopmental and neuropsychiatric disorders characterized by impaired verbal communication and social interaction. The clinical and genetic complexities of the condition make it difficult to identify susceptibility factors, but two related studies now present robust evidence for a genetic involvement. The first, a genome-wide association study, identifies six single-nucleotide polymorphisms strongly associated with autism. These variants lie between two genes encoding neuronal cell-adhesion molecules (cadherins 9 and 10), suggesting possible involvement in ASD pathogenesis. The second study used copy number variation screens to identify genetic variants in two major gene pathways in children with ASDs. The changes are in the ubiquitin pathway, which has previously been associated with neurological disease, and in genes for neuronal cell-adhesion molecules.

Macroeconomic Effects of Financial Shocks

Abstract: In this paper we document the cyclical properties of U.S. firms' financial flows. Equity payouts are procyclical and debt payouts are countercyclical. We develop a model with explicit roles for debt and equity financing and explore how the observed dynamics of real and financial variables are affected by `financial shocks', that is, shocks that affect the firms' capacity to borrow. Standard productivity shocks can only partially explain the movements in real and financial variables. The addition of financial shocks brings the model much closer to the data. The recent events in the financial sector show up clearly in our model as a tightening of firms' financing conditions causing the GDP decline in 2008-09. Our analysis also suggests that the downturns in 1990-91 and 2001 were strongly influenced by changes in credit conditions.

The utility of simulation in medical education: what is the evidence?

Abstract: Medical schools and residencies are currently facing a shift in their teaching paradigm. The increasing amount of medical information and research makes it difficult for medical education to stay current in its curriculum. As patients become increasingly concerned that students and residents are "practicing" on them, clinical medicine is becoming focused more on patient safety and quality than on bedside teaching and education. Educators have faced these challenges by restructuring curricula, developing small-group sessions, and increasing self-directed learning and independent research. Nevertheless, a disconnect still exists between the classroom and the clinical environment. Many students feel that they are inadequately trained in history taking, physical examination, diagnosis, and management. Medical simulation has been proposed as a technique to bridge this educational gap. This article reviews the evidence for the utility of simulation in medical education. We conducted a MEDLINE search of original articles and review articles related to simulation in education with key words such as simulation, mannequin simulator, partial task simulator, graduate medical education, undergraduate medical education, and continuing medical education. Articles, related to undergraduate medical education, graduate medical education, and continuing medical education were used in the review. One hundred thirteen articles were included in this review. Simulation-based training was demonstrated to lead to clinical improvement in 2 areas of simulation research. Residents trained on laparoscopic surgery simulators showed improvement in procedural performance in the operating room. The other study showed that residents trained on simulators were more likely to adhere to the advanced cardiac life support protocol than those who received standard training for cardiac arrest patients. In other areas of medical training, simulation has been demonstrated to lead to improvements in medical knowledge, comfort in procedures, and improvements in performance during retesting in simulated scenarios. Simulation has also been shown to be a reliable tool for assessing learners and for teaching topics such as teamwork and communication. Only a few studies have shown direct improvements in clinical outcomes from the use of simulation for training. Multiple studies have demonstrated the effectiveness of simulation in the teaching of basic science and clinical knowledge, procedural skills, teamwork, and communication as well as assessment at the undergraduate and graduate medical education levels. As simulation becomes increasingly prevalent in medical school and resident education, more studies are needed to see if simulation training improves patient outcomes.

Software Architecture: Foundations, Theory, and Practice

Abstract: Software architecture has become a centerpiece subject for software engineers, both researchers and practitioners alike. At the heart of every software system is its software architecture, i.e., "the set of principal design decisions about the system". Architecture permeates all major facets of a software system, for principal design decisions may potentially be made at any time during a system's lifetime, and potentially by any stakeholder. Such decisions encompass structural concerns, such as the system's high-level building blocks---components, connectors, and configurations; the system's deployment; the system's non-functional properties; and the system's evolution patterns, including runtime adaptation. Software architectures found particularly useful for families of systems---product lines---are often codified into architectural patterns, architectural styles, and reusable, parameterized reference architectures. This tutorial affords the participant an extensive treatment of the field of software architecture, its foundation, principles, and elements, including those mentioned above. Additionally, the tutorial introduces the participants to the state-of-the-art as well as the state-of-the-practice in software architecture, and looks at emerging and likely future trends in this field. The discussion is illustrated with numerous real-world examples. One example given prominent treatment is the architecture of the World Wide Web and its underlying architectural style, REpresentational State Transfer (REST).

Mitochondrial glutathione, a key survival antioxidant.

Abstract: Mitochondria are the primary intracellular site of oxygen consumption and the major source of reactive oxygen species (ROS), most of them originating from the mitochondrial respiratory chain Among the arsenal of antioxidants and detoxifying enzymes existing in mitochondria, mitochondrial glutathione (mGSH) emerges as the main line of defense for the maintenance of the appropriate mitochondrial redox environment to avoid or repair oxidative modifications leading to mitochondrial dysfunction and cell death mGSH importance is based not only on its abundance, but also on its versatility to counteract hydrogen peroxide, lipid hydroperoxides, or xenobiotics, mainly as a cofactor of enzymes such as glutathione peroxidase or glutathione-S-transferase (GST) Many death-inducing stimuli interact with mitochondria, causing oxidative stress; in addition, numerous pathologies are characterized by a consistent decrease in mGSH levels, which may sensitize to additional insults From the evaluation of mGSH inf

Mitochondrial bioenergetic deficit precedes Alzheimer's pathology in female mouse model of Alzheimer's disease

Abstract: Mitochondrial dysfunction has been proposed to play a pivotal role in neurodegenerative diseases, including Alzheimer's disease (AD). To address whether mitochondrial dysfunction precedes the development of AD pathology, we conducted mitochondrial functional analyses in female triple transgenic Alzheimer's mice (3xTg-AD) and age-matched nontransgenic (nonTg). Mitochondrial dysfunction in the 3xTg-AD brain was evidenced by decreased mitochondrial respiration and decreased pyruvate dehydrogenase (PDH) protein level and activity as early as 3 months of age. 3xTg-AD mice also exhibited increased oxidative stress as manifested by increased hydrogen peroxide production and lipid peroxidation. Mitochondrial amyloid beta (Aβ) level in the 3xTg-AD mice was significantly increased at 9 months and temporally correlated with increased level of Aβ binding to alcohol dehydrogenase (ABAD). Embryonic neurons derived from 3xTg-AD mouse hippocampus exhibited significantly decreased mitochondrial respiration and increased glycolysis. Results of these analyses indicate that compromised mitochondrial function is evident in embryonic hippocampal neurons, continues unabated in females throughout the reproductive period, and is exacerbated during reproductive senescence. In nontransgenic control mice, oxidative stress was coincident with reproductive senescence and accompanied by a significant decline in mitochondrial function. Reproductive senescence in the 3xTg-AD mouse brain markedly exacerbated mitochondrial dysfunction. Collectively, the data indicate significant mitochondrial dysfunction occurs early in AD pathogenesis in a female AD mouse model. Mitochondrial dysfunction provides a plausible mechanistic rationale for the hypometabolism in brain that precedes AD diagnosis and suggests therapeutic targets for prevention of AD.

When Are Outside Directors Effective

Abstract: This paper uses recent regulations that have required some companies to increase the number of outside directors on their boards to generate estimates of the effect of board independence on performance that are largely free from endogeneity problems. Our main finding is that the effectiveness of outside directors depends on the cost of acquiring information about the firm: when the cost of acquiring information is low, performance increases when outsiders are added to the board, and when the cost of information is high, performance worsens when outsiders are added to the board. The estimates provide some of the cleanest estimates to date that board independence matters, and the finding that board effectiveness depends on information cost supports a nascent theoretical literature emphasizing information asymmetry. We also find that firms compose their boards as if they understand that outsider effectiveness varies with information costs.

Radical Innovation Across Nations: The Preeminence of Corporate Culture

Abstract: Radical innovation is an important driver of the growth, success, and wealth of firms and nations. Because of its importance, authors across various disciplines have proposed many theories about the drivers of such innovation, including government policy and labor, capital, and culture at the national level. The authors contrast these theories with one based on the corporate culture of the firm. They test their theory using survey and archival data from 759 firms across 17 major economies of the world. The results suggest the following: First, among the factors studied, corporate culture is the strongest driver of radical innovation across nations; culture consists of three attitudes and three practices. Second, the commercialization of radical innovations translates into a firm's financial performance; it is a stronger predictor of financial performance than other popular measures, such as patents. The authors discuss the implications of these findings for research and practice.

Learning and generalization of motor skills by learning from demonstration

Abstract: We provide a general approach for learning robotic motor skills from human demonstration. To represent an observed movement, a non-linear differential equation is learned such that it reproduces this movement. Based on this representation, we build a library of movements by labeling each recorded movement according to task and context (e.g., grasping, placing, and releasing). Our differential equation is formulated such that generalization can be achieved simply by adapting a start and a goal parameter in the equation to the desired position values of a movement. For object manipulation, we present how our framework extends to the control of gripper orientation and finger position. The feasibility of our approach is demonstrated in simulation as well as on the Sarcos dextrous robot arm. The robot learned a pick-and-place operation and a water-serving task and could generalize these tasks to novel situations.