Showing papers by "University of Southern California published in 2011"

Integrated genomic analyses of ovarian carcinoma

Abstract: A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease

Abstract: Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

Brainstorm: a user-friendly application for MEG/EEG analysis

Abstract: Brainstorm is a collaborative open-source application dedicated to magnetoencephalography (MEG) and electroencephalography (EEG) data visualization and processing, with an emphasis on cortical source estimation techniques and their integration with anatomical magnetic resonance imaging (MRI) data. The primary objective of the software is to connect MEG/EEG neuroscience investigators with both the best-established and cutting-edge methods through a simple and intuitive graphical user interface (GUI).

Building Better Causal Theories: A Fuzzy Set Approach to Typologies in Organization Research

Abstract: Typologies are an important way of organizing the complex cause-effect relationships that are key building blocks of the strategy and organization literatures. Here, I develop a novel theoretical perspective on causal core and periphery, which is based on how elements of a configuration are connected to outcomes. Using data on hightechnology firms, I empirically investigate configurations based on the Miles and Snow typology using fuzzy set qualitative comparative analysis (fsQCA). My findings show how the theoretical perspective developed here allows for a detailed analysis of causal core, periphery, and asymmetry, shifting the focus to midrange theories of causal processes.

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

Abstract: 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.

A decade of exploring the cancer epigenome — biological and translational implications

Abstract: The past decade has highlighted the central role of epigenetic processes in cancer causation, progression and treatment. Next-generation sequencing is providing a window for visualizing the human epigenome and how it is altered in cancer. This view provides many surprises, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism. Epigenetic alterations are leading candidates for the development of specific markers for cancer detection, diagnosis and prognosis. The enzymatic processes that control the epigenome present new opportunities for deriving therapeutic strategies designed to reverse transcriptional abnormalities that are inherent to the cancer epigenome.

Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders.

Abstract: The neurovascular unit (NVU) comprises brain endothelial cells, pericytes or vascular smooth muscle cells, glia and neurons. The NVU controls blood-brain barrier (BBB) permeability and cerebral blood flow, and maintains the chemical composition of the neuronal 'milieu', which is required for proper functioning of neuronal circuits. Recent evidence indicates that BBB dysfunction is associated with the accumulation of several vasculotoxic and neurotoxic molecules within brain parenchyma, a reduction in cerebral blood flow, and hypoxia. Together, these vascular-derived insults might initiate and/or contribute to neuronal degeneration. This article examines mechanisms of BBB dysfunction in neurodegenerative disorders, notably Alzheimer's disease, and highlights therapeutic opportunities relating to these neurovascular deficits.

Advancing a conceptual model of evidence-based practice implementation in public service sectors.

Abstract: Implementation science is a quickly growing discipline. Lessons learned from business and medical settings are being applied but it is unclear how well they translate to settings with different historical origins and customs (e.g., public mental health, social service, alcohol/drug sectors). The purpose of this paper is to propose a multi-level, four phase model of the implementation process (i.e., Exploration, Adoption/Preparation, Implementation, Sustainment), derived from extant literature, and apply it to public sector services. We highlight features of the model likely to be particularly important in each phase, while considering the outer and inner contexts (i.e., levels) of public sector service systems.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Mapping the Moral Domain

Abstract: The moral domain is broader than the empathy and justice concerns assessed by existing measures of moral competence, and it is not just a subset of the values assessed by value inventories. To fill the need for reliable and theoretically grounded measurement of the full range of moral concerns, we developed the Moral Foundations Questionnaire on the basis of a theoretical model of 5 universally available (but variably developed) sets of moral intuitions: Harm/Care, Fairness/Reciprocity, Ingroup/Loyalty, Authority/Respect, and Purity/Sanctity. We present evidence for the internal and external validity of the scale and the model, and in doing so we present new findings about morality: (a) Comparative model fitting of confirmatory factor analyses provides empirical justification for a 5-factor structure of moral concerns; (b) convergent/discriminant validity evidence suggests that moral concerns predict personality features and social group attitudes not previously considered morally relevant; and (c) we establish pragmatic validity of the measure in providing new knowledge and research opportunities concerning demographic and cultural differences in moral intuitions. These analyses provide evidence for the usefulness of Moral Foundations Theory in simultaneously increasing the scope and sharpening the resolution of psychological views of morality.

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease.

Abstract: The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease

Abstract: We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 - 10'8 and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.

Genome-wide association study identifies five new schizophrenia loci

Abstract: We examined the role of common genetic variation in schizophrenia in a genome-wide association study of substantial size: a stage 1 discovery sample of 21,856 individuals of European ancestry and a stage 2 replication sample of 29,839 independent subjects. The combined stage 1 and 2 analysis yielded genome-wide significant associations with schizophrenia for seven loci, five of which are new (1p21.3, 2q32.3, 8p23.2, 8q21.3 and 10q24.32-q24.33) and two of which have been previously implicated (6p21.32-p22.1 and 18q21.2). The strongest new finding (P = 1.6 x 10(-11)) was with rs1625579 within an intron of a putative primary transcript for MIR137 (microRNA 137), a known regulator of neuronal development. Four other schizophrenia loci achieving genome-wide significance contain predicted targets of MIR137, suggesting MIR137-mediated dysregulation as a previously unknown etiologic mechanism in schizophrenia. In a joint analysis with a bipolar disorder sample (16,374 affected individuals and 14,044 controls), three loci reached genome-wide significance: CACNA1C (rs4765905, P = 7.0 x 10(-9)), ANK3 (rs10994359, P = 2.5 x 10(-8)) and the ITIH3-ITIH4 region (rs2239547, P = 7.8 x 10(-9)).

New definition for periprosthetic joint infection: from the Workgroup of the Musculoskeletal Infection Society.

Abstract: Based on the proposed criteria, definite PJI exists when: (1) There is a sinus tract communicating with the prosthesis; or (2) A pathogen is isolated by culture from at least two separate tissue or fluid samples obtained from the affected prosthetic joint; or (3) Four of the following six criteria exist: (a) Elevated serum erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration, (b) Elevated synovial leukocyte count, (c) Elevated synovial neutrophil percentage (PMN%), (d) Presence of purulence in the affected joint, (e) Isolation of a microorganism in one culture of periprosthetic tissue or fluid, or (f) Greater than five neutrophils per high-power field in five high-power fields observed from histologic analysis of periprosthetic tissue at ×400 magnification. PJI may be present if fewer than four of these criteria are met.

The World’s Technological Capacity to Store, Communicate, and Compute Information

Abstract: We estimated the world’s technological capacity to store, communicate, and compute information, tracking 60 analog and digital technologies during the period from 1986 to 2007. In 2007, humankind was able to store 2.9 × 10 20 optimally compressed bytes, communicate almost 2 × 10 21 bytes, and carry out 6.4 × 10 18 instructions per second on general-purpose computers. General-purpose computing capacity grew at an annual rate of 58%. The world’s capacity for bidirectional telecommunication grew at 28% per year, closely followed by the increase in globally stored information (23%). Humankind’s capacity for unidirectional information diffusion through broadcasting channels has experienced comparatively modest annual growth (6%). Telecommunication has been dominated by digital technologies since 1990 (99.9% in digital format in 2007), and the majority of our technological memory has been in digital format since the early 2000s (94% digital in 2007).

A User's Guide to the Encyclopedia of DNA Elements (ENCODE)

Abstract: The mission of the Encyclopedia of DNA Elements (ENCODE) Project is to enable the scientific and medical communities to interpret the human genome sequence and apply it to understand human biology and improve health. The ENCODE Consortium is integrating multiple technologies and approaches in a collective effort to discover and define the functional elements encoded in the human genome, including genes, transcripts, and transcriptional regulatory regions, together with their attendant chromatin states and DNA methylation patterns. In the process, standards to ensure high-quality data have been implemented, and novel algorithms have been developed to facilitate analysis. Data and derived results are made available through a freely accessible database. Here we provide an overview of the project and the resources it is generating and illustrate the application of ENCODE data to interpret the human genome.

A phase III, randomized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lymphocyte stimulator, in patients with systemic lupus erythematosus

Abstract: Objective To assess the efficacy/safety of the B lymphocyte stimulator inhibitor belimumab plus standard therapy compared with placebo plus standard therapy in active systemic lupus erythematosus (SLE) Methods In a phase III, multicenter, randomized, placebo-controlled trial, 819 antinuclear antibody-positive or anti-double-stranded DNA-positive SLE patients with scores ≥6 on the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) version of the SLE Disease Activity Index (SLEDAI) were randomized in a 1:1:1 ratio to receive 1 mg/kg belimumab, 10 mg/kg belimumab, or placebo intravenously on days 0, 14, and 28 and then every 28 days for 72 weeks The primary efficacy end point was the SLE Responder Index (SRI) response rate at week 52 (an SRI response was defined as a ≥4-point reduction in SELENA-SLEDAI score, no new British Isles Lupus Assessment Group [BILAG] A organ domain score and no more than 1 new BILAG B score, and no worsening in physician's global assessment score versus baseline) Results Belimumab at 10 mg/kg plus standard therapy met the primary efficacy end point, generating a significantly greater SRI response at week 52 compared with placebo (432% versus 335%; P = 0017) The rate with 1 mg/kg belimumab was 406% (P = 0089) Response rates at week 76 were 324%, 391%, and 385% with placebo, 1 mg/kg belimumab, and 10 mg/kg belimumab, respectively In post hoc sensitivity analyses evaluating higher SELENA-SLEDAI score thresholds, 10 mg/kg belimumab achieved better discrimination at weeks 52 and 76 Risk of severe flares over 76 weeks (based on the modified SLE Flare Index) was reduced with 1 mg/kg belimumab (34%) (P = 0023) and 10 mg/kg belimumab (23%) (P = 013) Serious and severe adverse events, including infections, laboratory abnormalities, malignancies, and deaths, were comparable across groups Conclusion Belimumab plus standard therapy significantly improved SRI response rate, reduced SLE disease activity and severe flares, and was generally well tolerated in SLE

The Changing of the Boards: The Impact on Firm Valuation of Mandated Female Board Representation

Abstract: In 2003, a new law required that 40 percent of Norwegian firms’ directors be women – at the time only nine percent of directors were women. We use the pre-quota cross-sectional variation in female board representation to instrument for exogenous changes to corporate boards following the quota. We find that the constraint imposed by the quota caused a significant drop in the stock price at the announcement of the law and a large decline in Tobin’s Q over the following years, consistent with the idea that firms choose boards to maximize value. The quota led to younger and less experienced boards, increases in leverage and acquisitions, and deterioration in operating performance, consistent with less capable boards.

Anthropogenic Chemical Carbon Cycle for a Sustainable Future

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, millions of years, can new fossil fuels be formed naturally. The burning of our diminishing fossil fuel reserves is accompanied by large anthropogenic CO2 release, which is outpacing nature’s CO2 recycling capability, causing significant environmental harm. To supplement the natural carbon cycle, we have proposed and developed a feasible anthropogenic chemical recycling of carbon dioxide. Carbon dioxide is captured by absorption technologies from any natural or industrial source, from human activities, or even from the air itself. It can then be converted by feasible chemical transformations into fuels such as methanol, dimethyl ether, and varied products including synthetic hydrocarbons and even proteins for animal feed, thus supplementing our food chain. This concept of broad scope and framework is the basis of what we call...

Formation of nascent soot and other condensed-phase materials in flames

Abstract: Over the last two decades, our understanding of soot formation has evolved from an empirical, phenomenological description to an age of quantitative modeling for at least small fuel compounds. In this paper, we review the current state of knowledge of the fundamental sooting processes, including the chemistry of soot precursors, particle nucleation and mass/size growth. The discussion shows that though much progress has been made, critical gaps remain in many areas of our knowledge. We propose the roles of certain aromatic radicals resulting from localized π electron structures in particle nucleation and subsequent mass growth. The existence of these free radicals provides a rational explanation for the strong binding forces needed for forming initial clusters of polycyclic aromatic hydrocarbons. They may also explain a range of currently unexplained sooting phenomena, including the large amount of aliphatics observed in nascent soot formed in laminar premixed flames and the mass growth of soot in the absence of gas-phase H atoms. While the above suggestions are inspired, to an extent, by recent theoretical findings from the materials research community, this paper also demonstrates that the knowledge garnered through our longstanding interest in soot formation may well be carried over to flame synthesis of functional nanomaterials for clean and renewable energy applications. In particular, work on flame-synthesized thin films of nanocrystalline titania illustrates how our combustion knowledge might be useful for developing advanced yet inexpensive thin-film solar cells and chemical sensors for detecting gaseous air pollutants.

Coronary-Artery Bypass Surgery in Patients with Left Ventricular Dysfunction

Abstract: The primary outcome occurred in 244 patients (41%) in the medical-therapy group and 218 (36%) in the CABG group (hazard ratio with CABG, 0.86; 95% confidence interval [CI], 0.72 to 1.04; P = 0.12). A total of 201 patients (33%) in the medicaltherapy group and 168 (28%) in the CABG group died from an adjudicated cardiovascular cause (hazard ratio with CABG, 0.81; 95% CI, 0.66 to 1.00; P = 0.05). Death from any cause or hospitalization for cardiovascular causes occurred in 411 patients (68%) in the medical-therapy group and 351 (58%) in the CABG group (hazard ratio with CABG, 0.74; 95% CI, 0.64 to 0.85; P<0.001). By the end of the followup period (median, 56 months), 100 patients in the medical-therapy group (17%) underwent CABG, and 555 patients in the CABG group (91%) underwent CABG. Conclusions In this randomized trial, there was no significant difference between medical therapy alone and medical therapy plus CABG with respect to the primary end point of death from any cause. Patients assigned to CABG, as compared with those assigned to medical therapy alone, had lower rates of death from cardiovascular causes and of death from any cause or hospitalization for cardiovascular causes. (Funded by the National Heart, Lung, and Blood Institute and Abbott Laboratories; STICH ClinicalTrials.gov number, NCT00023595.)

Harnessing neuroplasticity for clinical applications

Abstract: Neuroplasticity can be defined as the ability of the nervous system to respond to intrinsic or extrinsic stimuli by reorganizing its structure, function and connections. Major advances in the understanding of neuroplasticity have to date yielded few established interventions. To advance the translation of neuroplasticity research towards clinical applications, the National Institutes of Health Blueprint for Neuroscience Research sponsored a workshop in 2009. Basic and clinical researchers in disciplines from central nervous system injury/stroke, mental/addictive disorders, paediatric/developmental disorders and neurodegeneration/ageing identified cardinal examples of neuroplasticity, underlying mechanisms, therapeutic implications and common denominators. Promising therapies that may enhance training-induced cognitive and motor learning, such as brain stimulation and neuropharmacological interventions, were identified, along with questions of how best to use this body of information to reduce human disability. Improved understanding of adaptive mechanisms at every level, from molecules to synapses, to networks, to behaviour, can be gained from iterative collaborations between basic and clinical researchers. Lessons can be gleaned from studying fields related to plasticity, such as development, critical periods, learning and response to disease. Improved means of assessing neuroplasticity in humans, including biomarkers for predicting and monitoring treatment response, are needed. Neuroplasticity occurs with many variations, in many forms, and in many contexts. However, common themes in plasticity that emerge across diverse central nervous system conditions include experience dependence, time sensitivity and the importance of motivation and attention. Integration of information across disciplines should enhance opportunities for the translation of neuroplasticity and circuit retraining research into effective clinical therapies.

Plasmon Resonant Enhancement of Photocatalytic Water Splitting Under Visible Illumination

Abstract: We demonstrate plasmonic enhancement of photocatalytic water splitting under visible illumination by integrating strongly plasmonic Au nanoparticles with strongly catalytic TiO2. Under visible illumination, we observe enhancements of up to 66× in the photocatalytic splitting of water in TiO2 with the addition of Au nanoparticles. Above the plasmon resonance, under ultraviolet radiation we observe a 4-fold reduction in the photocatalytic activity. Electromagnetic simulations indicate that the improvement of photocatalytic activity in the visible range is caused by the local electric field enhancement near the TiO2 surface, rather than by the direct transfer of charge between the two materials. Here, the near-field optical enhancement increases the electron-hole pair generation rate at the surface of the TiO2, thus increasing the amount of photogenerated charge contributing to catalysis. This mechanism of enhancement is particularly effective because of the relatively short exciton diffusion length (or minority carrier diffusion length), which otherwise limits the photocatalytic performance. Our results suggest that enhancement factors many times larger than this are possible if this mechanism can be optimized.

Knowledge Collaboration in Online Communities

Abstract: Online communities (OCs) are a virtual organizational form in which knowledge collaboration can occur in unparalleled scale and scope, in ways not heretofore theorized. For example, collaboration can occur among people not known to each other, who share different interests and without dialogue. An exploration of this organizational form can fundamentally change how we theorize about knowledge collaboration among members of organizations. We argue that a fundamental characteristic of OCs that affords collaboration is their fluidity. This fluidity engenders a dynamic flow of resources in and out of the community---resources such as passion, time, identity, social disembodiment of ideas, socially ambiguous identities, and temporary convergence. With each resource comes both a negative and positive consequence, creating a tension that fluctuates with changes in the resource. We argue that the fluctuations in tensions can provide an opportunity for knowledge collaboration when the community responds to these tensions in ways that encourage interactions to be generative rather than constrained. After offering numerous examples of such generative responses, we suggest that this form of theorizing---induced by online communities---has implications for theorizing about the more general case of knowledge collaboration in organizations.

The Arabidopsis lyrata genome sequence and the basis of rapid genome size change

Abstract: We present the 207 Mb genome sequence of the outcrosser Arabidopsis lyrata, which diverged from the self-fertilizing species A. thaliana about 10 million years ago. It is generally assumed that the much smaller A. thaliana genome, which is only 125 Mb, constitutes the derived state for the family. Apparent genome reduction in this genus can be partially attributed to the loss of DNA from large-scale rearrangements, but the main cause lies in the hundreds of thousands of small deletions found throughout the genome. These occurred primarily in non-coding DNA and transposons, but protein-coding multi-gene families are smaller in A. thaliana as well. Analysis of deletions and insertions still segregating in A. thaliana indicates that the process of DNA loss is ongoing, suggesting pervasive selection for a smaller genome.

Resolvins and Protectins in Inflammation-Resolution

Abstract: The critical role of inflammatory processes in health and disease has long been recognized,1 yet the detailed molecular mechanisms and biological events that regulate the progression and resolution of inflammation remain of interest. A number of recent investigations have provided strong evidence that the resolution of inflammation is not a passive process, as believed earlier.2–4 Instead, resolution is a biosynthetically active process, regulated by biochemical mediators and receptor-signaling pathways, and driven by specialized pro-resolving mediators (SPM). In particular, following a number of findings by Serhan and his group, the authors and their collaborators introduced and systematically investigated a number of SPM derived from polyunsaturated fatty acids (PUFA), including lipoxins, E-series resolvins, D-series resolvins, protectins/neuroprotectins, and, most recently, maresins. This review summarizes efforts on the resolvins and protectins with an emphasis on the corresponding biochemical pathways. Additional reviews covering different aspects of these anti-inflammatory and pro-resolving lipid mediators,5 including immunology,6,7 pathology,8 biochemistry,9 pharmacology10 and chemistry11 are also available.6–9,12 1.1 The Inflammatory Response and the Resolution of Inflammation Localized acute inflammation is part of the host’s normal protective response to tissue injury and infection by invading microbial pathogens.1 Although this inflammatory response to a range of harmful stimuli is protective to the host, if kept uncontrolled it can result in a wide range of acute, chronic and systemic inflammatory disorders. Indeed, some of the most common and difficult to treat diseases are linked to excessive, uncontrollable, or chronic inflammation, including: cardiovascular disease, rheumatoid arthritis, periodontal disease, asthma, diabetes, inflammatory bowel disease (IBD), as well as neurological disorders such as Alzheimer’s disease and age-related macular degeneration (AMD).1,13,14 Although the involvement of inflammatory pathways in the initiation of all of these diseases is well established, the specific role by which inflammation contributes to their pathogenesis is not fully understood. The recent findings that the resolution of inflammation is an active process2–4,15 have provided new insights and created new paradigms for understanding and treating these conditions. The key role of a number of lipid mediators in the initiation of the inflammatory response and the subsequent progression towards resolution is illustrated in Fig. 1. Among the first signaling events following microbial infection or tissue injury, is the release of pro-inflammatory lipid mediators, such as leukotrienes (LTs) and prostaglandins (PGs) that launch a series of signaling cascades with the ultimate goal of destroying the invading pathogens and repairing the damaged tissue.16–18 Thus, the biosynthesis and release of the potent chemotactic agent leukotriene B4 (LTB4) promotes the recruitment of neutrophils (PMNs) to the inflamed tissue, while the formation of prostaglandins E2 and D2 (PGE2 and PGD2)15 further accelerates the inflammatory process, ultimately resulting in a condition of acute inflammation. Despite its critical host-protective function, acute inflammation is not sustainable over a prolonged period of time, giving rise to disruptive conditions of chronic inflammation that may be responsible for the pathogenesis of a wide range of diseases, that can be attributed to a failure of resolution.19 Typically, the therapeutic treatment of such conditions involves the inhibition of pro-inflammatory mediators, but in many cases such approaches are often not very effective. Figure 1 From initiation of acute inflammation to resolution: The inflammatory response to microbial infection and tissue injury, and the role of selected cell types and specialized pro-resolving lipid mediators. The recognition of the proactive nature of the resolution of inflammation has revealed alternative therapeutic paradigms based on resolving acute inflammation and preventing the onset of chronic inflammation.19 Indeed, a number of endogenous lipid mediators identified are able to act in this manner, suggesting a lipid mediator class switching3 from the initial actions of pro-inflammatory lipid mediators, i.e. leukotriene and prostaglandins, to the anti-inflammatory and pro-resolving actions of lipoxins, resolvins, protectins and maresins, which are discussed in this review. Each family of these pro-resolving mediators exert specialized actions, including blocking neutrophil recruitment, promoting the recruitment and activation of monocytes, as well as mediating the nonphlogistic phagocytosis and lymphatic clearance of apoptotic neutrophils by activated macrophages. Eventually, through the combined actions of these mediators, the resolution of inflammation is completed and homeostasis is reached. In this regard, it was important to introduce precise definitions for resolution mechanisms and indices19–21 that also permitted the first information that certain agents can be resolution-toxic.22–24

STOMP: Stochastic trajectory optimization for motion planning

Abstract: We present a new approach to motion planning using a stochastic trajectory optimization framework. The approach relies on generating noisy trajectories to explore the space around an initial (possibly infeasible) trajectory, which are then combined to produced an updated trajectory with lower cost. A cost function based on a combination of obstacle and smoothness cost is optimized in each iteration. No gradient information is required for the particular optimization algorithm that we use and so general costs for which derivatives may not be available (e.g. costs corresponding to constraints and motor torques) can be included in the cost function. We demonstrate the approach both in simulation and on a mobile manipulation system for unconstrained and constrained tasks. We experimentally show that the stochastic nature of STOMP allows it to overcome local minima that gradient-based methods like CHOMP can get stuck in.