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Showing papers by "University of Gothenburg published in 2009"


Journal ArticleDOI
TL;DR: The Uppsala internationalization process model was revisited in the light of changes in business practices and theoretical advances that have been made since 1977 as mentioned in this paper, and the change mechanisms in the revised model are essentially the same as those in the original version, although they add trust-building and knowledge creation, the latter to recognize the fact that new knowledge is developed in relationships.
Abstract: The Uppsala internationalization process model is revisited in the light of changes in business practices and theoretical advances that have been made since 1977. Now the business environment is viewed as a web of relationships, a network, rather than as a neoclassical market with many independent suppliers and customers. Outsidership, in relation to the relevant network, more than psychic distance, is the root of uncertainty. The change mechanisms in the revised model are essentially the same as those in the original version, although we add trust-building and knowledge creation, the latter to recognize the fact that new knowledge is developed in relationships.

3,700 citations


Journal ArticleDOI
TL;DR: In this article, an overview of the atmospheric degradation mechanisms for SOA precursors, gas-particle partitioning theory and analytical techniques used to determine the chemical composition of SOA is presented.
Abstract: Secondary organic aerosol (SOA) accounts for a significant fraction of ambient tropospheric aerosol and a detailed knowledge of the formation, properties and transformation of SOA is therefore required to evaluate its impact on atmospheric processes, climate and human health. The chemical and physical processes associated with SOA formation are complex and varied, and, despite considerable progress in recent years, a quantitative and predictive understanding of SOA formation does not exist and therefore represents a major research challenge in atmospheric science. This review begins with an update on the current state of knowledge on the global SOA budget and is followed by an overview of the atmospheric degradation mechanisms for SOA precursors, gas-particle partitioning theory and the analytical techniques used to determine the chemical composition of SOA. A survey of recent laboratory, field and modeling studies is also presented. The following topical and emerging issues are highlighted and discussed in detail: molecular characterization of biogenic SOA constituents, condensed phase reactions and oligomerization, the interaction of atmospheric organic components with sulfuric acid, the chemical and photochemical processing of organics in the atmospheric aqueous phase, aerosol formation from real plant emissions, interaction of atmospheric organic components with water, thermodynamics and mixtures in atmospheric models. Finally, the major challenges ahead in laboratory, field and modeling studies of SOA are discussed and recommendations for future research directions are proposed.

3,324 citations


Journal ArticleDOI
Lorenzo Galluzzi1, Lorenzo Galluzzi2, Lorenzo Galluzzi3, Stuart A. Aaronson4, John M. Abrams5, Emad S. Alnemri6, David W. Andrews7, Eric H. Baehrecke8, Nicolas G. Bazan9, Mikhail V. Blagosklonny10, Klas Blomgren11, Klas Blomgren12, Christoph Borner13, Dale E. Bredesen14, Dale E. Bredesen15, Catherine Brenner16, Maria Castedo3, Maria Castedo1, Maria Castedo2, John A. Cidlowski17, Aaron Ciechanover18, Gerald M. Cohen19, V De Laurenzi20, R De Maria21, Mohanish Deshmukh22, Brian David Dynlacht23, Wafik S. El-Deiry24, Richard A. Flavell25, Richard A. Flavell26, Simone Fulda27, Carmen Garrido28, Carmen Garrido1, Pierre Golstein16, Pierre Golstein1, Pierre Golstein29, Marie-Lise Gougeon30, Douglas R. Green, Hinrich Gronemeyer31, Hinrich Gronemeyer1, Hinrich Gronemeyer16, György Hajnóczky6, J. M. Hardwick32, Michael O. Hengartner33, Hidenori Ichijo34, Marja Jäättelä, Oliver Kepp2, Oliver Kepp1, Oliver Kepp3, Adi Kimchi35, Daniel J. Klionsky36, Richard A. Knight37, Sally Kornbluth38, Sharad Kumar, Beth Levine26, Beth Levine5, Stuart A. Lipton, Enrico Lugli17, Frank Madeo39, Walter Malorni21, Jean-Christophe Marine40, Seamus J. Martin41, Jan Paul Medema42, Patrick Mehlen16, Patrick Mehlen43, Gerry Melino19, Gerry Melino44, Ute M. Moll45, Ute M. Moll46, Eugenia Morselli3, Eugenia Morselli2, Eugenia Morselli1, Shigekazu Nagata47, Donald W. Nicholson48, Pierluigi Nicotera19, Gabriel Núñez36, Moshe Oren35, Josef M. Penninger49, Shazib Pervaiz50, Marcus E. Peter51, Mauro Piacentini44, Jochen H. M. Prehn52, Hamsa Puthalakath53, Gabriel A. Rabinovich54, Rosario Rizzuto55, Cecília M. P. Rodrigues56, David C. Rubinsztein57, Thomas Rudel58, Luca Scorrano59, Hans-Uwe Simon60, Hermann Steller26, Hermann Steller61, J. Tschopp62, Yoshihide Tsujimoto63, Peter Vandenabeele64, Ilio Vitale3, Ilio Vitale1, Ilio Vitale2, Karen H. Vousden65, Richard J. Youle17, Junying Yuan66, Boris Zhivotovsky67, Guido Kroemer3, Guido Kroemer1, Guido Kroemer2 
French Institute of Health and Medical Research1, University of Paris-Sud2, Institut Gustave Roussy3, Icahn School of Medicine at Mount Sinai4, University of Texas Southwestern Medical Center5, Thomas Jefferson University6, McMaster University7, University of Massachusetts Medical School8, LSU Health Sciences Center New Orleans9, Roswell Park Cancer Institute10, Boston Children's Hospital11, University of Gothenburg12, University of Freiburg13, University of California, San Francisco14, Buck Institute for Research on Aging15, Centre national de la recherche scientifique16, National Institutes of Health17, Technion – Israel Institute of Technology18, University of Leicester19, University of Chieti-Pescara20, Istituto Superiore di Sanità21, University of North Carolina at Chapel Hill22, New York University23, University of Pennsylvania24, Yale University25, Howard Hughes Medical Institute26, University of Ulm27, University of Burgundy28, Aix-Marseille University29, Pasteur Institute30, University of Strasbourg31, Johns Hopkins University32, University of Zurich33, University of Tokyo34, Weizmann Institute of Science35, University of Michigan36, University College London37, Duke University38, University of Graz39, Ghent University40, Trinity College, Dublin41, University of Amsterdam42, University of Lyon43, University of Rome Tor Vergata44, Stony Brook University45, University of Göttingen46, Kyoto University47, Merck & Co.48, Austrian Academy of Sciences49, National University of Singapore50, University of Chicago51, Royal College of Surgeons in Ireland52, La Trobe University53, University of Buenos Aires54, University of Padua55, University of Lisbon56, University of Cambridge57, University of Würzburg58, University of Geneva59, University of Bern60, Rockefeller University61, University of Lausanne62, Osaka University63, University of California, San Diego64, University of Glasgow65, Harvard University66, Karolinska Institutet67
TL;DR: A nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls is provided and the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells is emphasized.
Abstract: Cell death is essential for a plethora of physiological processes, and its deregulation characterizes numerous human diseases Thus, the in-depth investigation of cell death and its mechanisms constitutes a formidable challenge for fundamental and applied biomedical research, and has tremendous implications for the development of novel therapeutic strategies It is, therefore, of utmost importance to standardize the experimental procedures that identify dying and dead cells in cell cultures and/or in tissues, from model organisms and/or humans, in healthy and/or pathological scenarios Thus far, dozens of methods have been proposed to quantify cell death-related parameters However, no guidelines exist regarding their use and interpretation, and nobody has thoroughly annotated the experimental settings for which each of these techniques is most appropriate Here, we provide a nonexhaustive comparison of methods to detect cell death with apoptotic or nonapoptotic morphologies, their advantages and pitfalls These guidelines are intended for investigators who study cell death, as well as for reviewers who need to constructively critique scientific reports that deal with cellular demise Given the difficulties in determining the exact number of cells that have passed the point-of-no-return of the signaling cascades leading to cell death, we emphasize the importance of performing multiple, methodologically unrelated assays to quantify dying and dead cells

2,218 citations


Journal ArticleDOI
TL;DR: Develop a cerebrospinal fluid biomarker signature for mild Alzheimer's disease (AD) in Alzheimer's Disease Neuroimaging Initiative (ADNI) subjects.
Abstract: If the clinical diagnosis of probable AD is imprecise with accuracy rates of approximately 90% or lower using established consensus criteria for probable AD, but definite AD requires autopsy confirmation, it is not surprising that diagnostic accuracy is lower at early and presymptomatic stages of AD.1–4 It is believed that the development of full-blown AD takes place over an approximately 20-year prodromal period, but this is difficult to determine in the absence of biomarkers that reliably signal the onset of nascent disease before the emergence of measurable cognitive impairments. Because intervention with disease-modifying therapies for AD is likely to be most efficacious before significant neurodegeneration has occurred, there is an urgent need for biomarker-based tests that enable a more accurate and early diagnosis of AD.5–7 Moreover, such tests could also improve monitoring AD progression, evaluation of new AD therapies, and enrichment of AD cohorts with specific subsets of AD subjects in clinical trials. The defining lesions of AD are neurofibrillary tangles and senile plaques formed, respectively, by neuronal accumulations of abnormal hyperphosphorylated tau filaments and extracellular deposits of amyloid β (Aβ) fibrils, mostly the 1 to 42 peptide (Aβ1-42), the least soluble of the known Aβ peptides produced from Aβ precursor protein by the action of various peptidases.1–3 Hence, for these and other reasons summarized in consensus reports on AD biomarkers, cerebrospinal fluid (CSF), total tau (t-tau), and Aβ were identified as being among the most promising and informative AD biomarkers.5,6 Increased levels of tau in CSF are thought to occur after its release from damaged and dying neurons that harbor dystrophic tau neurites and tangles, whereas reduced CSF levels of Aβ1-42 are believed to result from large-scale accumulation of this least soluble of Aβ peptides into insoluble plaques in the AD brain. The combination of increased CSF concentrations of t-tau and phosphotau (p-tau) species and decreased concentrations of Aβ1-42 are considered to be a pathological CSF biomarker signature that is diagnostic for AD.5,6,8,9 Notably, recent studies have provided compelling preliminary data to suggest that this combination of CSF tau and Aβ biomarker changes may predict the conversion to AD in mild cognitive impairment (MCI) subjects.10 Thus, an increase in levels of CSF tau associated with a decline in levels of CSF Aβ1-42 may herald the onset of AD before it becomes clinically manifest. However, before the utility of CSF Aβ1-42 and tau concentrations for diagnosis of AD can be established, it is critical to standardize the methodology for their measurement.5–8,10 For example, among the published studies of CSF tau and Aβ, there is considerable variability in the observed levels of these analytes, as well as their diagnostic sensitivity and specificity. This is attributable to variability in analytical methodology standardization and other factors that differ between studies of the same CSF analytes in similar but not identical cohorts.5–7 The Alzheimer’s Disease Neuroimaging Initiative (ADNI) was launched in 2004 to address these and other limitations in AD biomarkers (see reviews in Shaw and colleagues7 and Mueller and coauthors,11 and the ADNI Web site [http://www.adni-info.org/index] where the ADNI grant and all ADNI data are posted for public access). To this end, the Biomarker Core of ADNI conducts studies on ADNI-derived CSF samples to measure CSF Aβ1-42, t-tau, and p-tau (tau phosphorylated at threonine181 [p-tau181p]) in standardized assays. Evaluation of CSF obtained at baseline evaluation of 416 of the 819 ADNI subjects is now complete, and we report here our findings on the performance of these tests using a standardized multiplex immunoassay system that measures the biomarkers simultaneously in the same sample aliquot in ADNI subjects and in an independent cohort of autopsy-confirmed AD cases.

1,912 citations


Journal ArticleDOI
TL;DR: In patients undergoing hemodialysis, the initiation of treatment with rosuvastatin lowered the LDL cholesterol level but had no significant effect on the composite primary end point of death from cardiovascular causes, nonf fatal myocardial infarction, or nonfatal stroke.
Abstract: BACKGROUND: Statins reduce the incidence of cardiovascular events in patients at high cardiovascular risk. However, a benefit of statins in such patients who are undergoing hemodialysis has not bee ...

1,789 citations


Journal ArticleDOI
TL;DR: This classification of the different platelet concentrates into four categories, depending on their leucocyte and fibrin content, should help to elucidate successes and failures that have occurred so far, as well as providing an objective approach for the further development of these techniques.

1,454 citations


Journal ArticleDOI
19 Mar 2009-Nature
TL;DR: Rather than one or two domestication events leading to the extant baker’s yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.
Abstract: Since the completion of the genome sequence of Saccharomyces cerevisiae in 1996 (refs 1, 2), there has been a large increase in complete genome sequences, accompanied by great advances in our understanding of genome evolution. Although little is known about the natural and life histories of yeasts in the wild, there are an increasing number of studies looking at ecological and geographic distributions, population structure and sexual versus asexual reproduction. Less well understood at the whole genome level are the evolutionary processes acting within populations and species that lead to adaptation to different environments, phenotypic differences and reproductive isolation. Here we present one- to fourfold or more coverage of the genome sequences of over seventy isolates of the baker's yeast S. cerevisiae and its closest relative, Saccharomyces paradoxus. We examine variation in gene content, single nucleotide polymorphisms, nucleotide insertions and deletions, copy numbers and transposable elements. We find that phenotypic variation broadly correlates with global genome-wide phylogenetic relationships. S. paradoxus populations are well delineated along geographic boundaries, whereas the variation among worldwide S. cerevisiae isolates shows less differentiation and is comparable to a single S. paradoxus population. Rather than one or two domestication events leading to the extant baker's yeasts, the population structure of S. cerevisiae consists of a few well-defined, geographically isolated lineages and many different mosaics of these lineages, supporting the idea that human influence provided the opportunity for cross-breeding and production of new combinations of pre-existing variations.

1,425 citations


Journal ArticleDOI
TL;DR: Some indications exist that surface topography influences bone response at the nanometre level and the majority of published papers present an inadequate surface characterization.
Abstract: European Association for Osseointegration; 19-22 February 2009, Pfaffikon, Switzerland; 2nd Consensus Conference

1,187 citations


Journal ArticleDOI
22 Jul 2009-JAMA
TL;DR: This multicenter study found that CSF Abeta42, T-t Tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies.
Abstract: Context Small single-center studies have shown that cerebrospinal fluid (CSF) biomarkers may be useful to identify incipient Alzheimer disease (AD) in patients with mild cognitive impairment (MCI), but large-scale multicenter studies have not been conducted. Objective To determine the diagnostic accuracy of CSF beta-amyloid(1-42) (A beta 42), total tau protein (T-tau), and tau phosphorylated at position threonine 181 (P-tau) for predicting incipient AD in patients with MCI. Design, Setting, and Participants The study had 2 parts: a cross-sectional study involving patients with AD and controls to identify cut points, followed by a prospective cohort study involving patients with MCI, conducted 1990-2007. A total of 750 individuals with MCI, 529 with AD, and 304 controls were recruited by 12 centers in Europe and the United States. Individuals with MCI were followed up for at least 2 years or until symptoms had progressed to clinical dementia. Main Outcome Measures Sensitivity, specificity, positive and negative likelihood ratios (LRs) of CSF A beta 42, T-tau, and P-tau for identifying incipient AD. Results During follow-up, 271 participants with MCI were diagnosed with AD and 59 with other dementias. The A beta 42 assay in particular had considerable intersite variability. Patients who developed AD had lower median A beta 42 (356; range, 96-1075 ng/L) and higher P-tau (81; range, 15-183 ng/L) and T-tau (582; range, 83-2174 ng/L) levels than MCI patients who did not develop AD during follow-up (579; range, 1211420 ng/L for A beta 42; 53; range, 15-163 ng/L for P-tau; and 294; range, 31-2483 ng/L for T-tau, P < .001). The area under the receiver operating characteristic curve was 0.78 (95% confidence interval [CI], 0.75-0.82) for A beta 42, 0.76 (95% CI, 0.72-0.80) for P-tau, and 0.79 (95% CI, 0.76-0.83) for T-tau. Cut-offs with sensitivity set to 85% were defined in the AD and control groups and tested in the MCI group, where the combination of A beta 42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83% (95% CI, 78%-88%), specificity 72% (95% CI, 68%-76%), positive LR, 3.0 (95% CI, 2.5-3.4), and negative LR, 0.24 (95% CI, 0.21-0.28). The positive predictive value was 62% and the negative predictive value was 88%. Conclusions This multicenter study found that CSF A beta 42, T-tau, and P-tau identify incipient AD with good accuracy, but less accurately than reported from single-center studies. Intersite assay variability highlights a need for standardization of analytical techniques and clinical procedures. JAMA. 2009;302(4):385-393 (Less)

1,075 citations


Journal ArticleDOI
TL;DR: In this article, a comprehensive review of the status of the contemporary carbon cycle of the Arctic and its response to climate change is presented to clarify key uncertainties and vulnerabilities in the response of the carbon cycle in the Arctic to ongoing climatic change.
Abstract: The recent warming in the Arctic is affecting a broad spectrum of physical, ecological, and human/cultural systems that may be irreversible on century time scales and have the potential to cause rapid changes in the earth system. The response of the carbon cycle of the Arctic to changes in climate is a major issue of global concern, yet there has not been a comprehensive review of the status of the contemporary carbon cycle of the Arctic and its response to climate change. This review is designed to clarify key uncertainties and vulnerabilities in the response of the carbon cycle of the Arctic to ongoing climatic change. While it is clear that there are substantial stocks of carbon in the Arctic, there are also significant uncertainties associated with the magnitude of organic matter stocks contained in permafrost and the storage of methane hydrates beneath both subterranean and submerged permafrost of the Arctic. In the context of the global carbon cycle, this review demonstrates that the Arctic plays an important role in the global dynamics of both CO2 and CH4. Studies suggest that the Arctic has been a sink for atmospheric CO2 of between 0 and 0.8 Pg C/yr in recent decades, which is between 0% and 25% of the global net land/ocean flux during the 1990s. The Arctic is a substantial source of CH4 to the atmosphere (between 32 and 112 Tg CH4/yr), primarily because of the large area of wetlands throughout the region. Analyses to date indicate that the sensitivity of the carbon cycle of the Arctic during the remainder of the 21st century is highly uncertain. To improve the capability to assess the sensitivity of the carbon cycle of the Arctic to projected climate change, we recommend that (1) integrated regional studies be conducted to link observations of carbon dynamics to the processes that are likely to influence those dynamics, and (2) the understanding gained from these integrated studies be incorporated into both uncoupled and fully coupled carbon-climate modeling efforts. (Less)

953 citations


Journal ArticleDOI
TL;DR: During soft brush stroking, low-threshold unmyelinated mechanoreceptors (C-tactile), but not myelinated afferents, responded most vigorously at intermediate brushing velocities, which were perceived by subjects as being the most pleasant.
Abstract: Pleasant touch sensations may begin with neural coding in the periphery by specific afferents. We found that during soft brush stroking, low-threshold unmyelinated mechanoreceptors (C-tactile), but not myelinated afferents, responded most vigorously at intermediate brushing velocities (1-10 cm s(-1)), which were perceived by subjects as being the most pleasant. Our results indicate that C-tactile afferents constitute a privileged peripheral pathway for pleasant tactile stimulation that is likely to signal affiliative social body contact.

Journal ArticleDOI
TL;DR: In patients with locally advanced or high-risk local prostate cancer, addition of local radiotherapy to endocrine treatment halved the 10-year prostate-cancer-specific mortality, and substantially decreased overall mortality with fully acceptable risk of side-effects compared with endocrine Treatment alone.

Journal ArticleDOI
TL;DR: The clinical psychiatric presentation and important outcome measures of a large group of normal-intelligence adult patients with ASDs, characterized by impaired social interaction and non-verbal communication in adulthood as well as in childhood, are described.
Abstract: Individuals with autism spectrum disorders (ASDs) often display symptoms from other diagnostic categories. Studies of clinical and psychosocial outcome in adult patients with ASDs without concomitant intellectual disability are few. The objective of this paper is to describe the clinical psychiatric presentation and important outcome measures of a large group of normal-intelligence adult patients with ASDs. Autistic symptomatology according to the DSM-IV-criteria and the Gillberg & Gillberg research criteria, patterns of comorbid psychopathology and psychosocial outcome were assessed in 122 consecutively referred adults with normal intelligence ASDs. The subjects consisted of 5 patients with autistic disorder (AD), 67 with Asperger's disorder (AS) and 50 with pervasive developmental disorder not otherwise specified (PDD NOS). This study group consists of subjects pooled from two studies with highly similar protocols, all seen on an outpatient basis by one of three clinicians. Core autistic symptoms were highly prevalent in all ASD subgroups. Though AD subjects had the most pervasive problems, restrictions in non-verbal communication were common across all three subgroups and, contrary to current DSM criteria, so were verbal communication deficits. Lifetime psychiatric axis I comorbidity was very common, most notably mood and anxiety disorders, but also ADHD and psychotic disorders. The frequency of these diagnoses did not differ between the ASD subgroups or between males and females. Antisocial personality disorder and substance abuse were more common in the PDD NOS group. Of all subjects, few led an independent life and very few had ever had a long-term relationship. Female subjects more often reported having been bullied at school than male subjects. ASDs are clinical syndromes characterized by impaired social interaction and non-verbal communication in adulthood as well as in childhood. They also carry a high risk for co-existing mental health problems from a broad spectrum of disorders and for unfavourable psychosocial life circumstances. For the next revision of DSM, our findings especially stress the importance of careful examination of the exclusion criterion for adult patients with ASDs.

Journal ArticleDOI
TL;DR: In this paper, the authors investigated the environmental fate of active pharmaceutical ingredients in a major production area for the global bulk drug market, where water samples were taken from a common effluent treatment plant near Hyderabad, India, which receives process water from approximately 90 bulk drug manufacturers.
Abstract: Low levels of pharmaceuticals are detected in surface, ground, and drinking water worldwide. Usage and incorrect disposal have been considered the major environmental sources of these microcontaminants. Recent publications, however, suggest that wastewater from drug production can potentially be a source of much higher concentrations in certain locations. The present study investigated the environmental fate of active pharmaceutical ingredients in a major production area for the global bulk drug market. Water samples were taken from a common effluent treatment plant near Hyderabad, India, which receives process water from approximately 90 bulk drug manufacturers. Surface water was analyzed from the recipient stream and from two lakes that are not contaminated by the treatment plant. Water samples were also taken from wells in six nearby villages. The samples were analyzed for the presence of 12 pharmaceuticals with liquid chromatography-mass spectrometry. All wells were determined to be contaminated with drugs. Ciprofloxacin, enoxacin, cetirizine, terbinafine, and citalopram were detected at more than 1 microg/L in several wells. Very high concentrations of ciprofloxacin (14 mg/L) and cetirizine (2.1 mg/L) were found in the effluent of the treatment plant, together with high concentrations of seven additional pharmaceuticals. Very high concentrations of ciprofloxacin (up to 6.5 mg/L), cetirizine (up to 1.2 mg/L), norfloxacin (up to 0.52 mg/L), and enoxacin (up to 0.16 mg/L) were also detected in the two lakes, which clearly shows that the investigated area has additional environmental sources of insufficiently treated industrial waste. Thus, insufficient wastewater management in one of the world's largest centers for bulk drug production leads to unprecedented drug contamination of surface, ground, and drinking water. This raises serious concerns regarding the development of antibiotic resistance, and it creates a major challenge for producers and regulatory agencies to improve the situation.

Journal ArticleDOI
TL;DR: New sequence data and methods strongly uphold previous suggestions that Acoelomorpha is sister clade to all other bilaterian animals, find diminishing evidence for the placement of the enigmatic Xenoturbella within Deuterostomia, and place Cycliophora with Entoprocta and EctoproCTa.
Abstract: A clear picture of animal relationships is a prerequisite to understand how the morphological and ecological diversity of animals evolved over time. Among others, the placement of the acoelomorph flatworms, Acoela and Nemertodermatida, has fundamental implications for the origin and evolution of various animal organ systems. Their position, however, has been inconsistent in phylogenetic studies using one or several genes. Furthermore, Acoela has been among the least stable taxa in recent animal phylogenomic analyses, which simultaneously examine many genes from many species, while Nemertodermatida has not been sampled in any phylogenomic study. New sequence data are presented here from organisms targeted for their instability or lack of representation in prior analyses, and are analysed in combination with other publicly available data. We also designed new automated explicit methods for identifying and selecting common genes across different species, and developed highly optimized supercomputing tools to reconstruct relationships from gene sequences. The results of the work corroborate several recently established findings about animal relationships and provide new support for the placement of other groups. These new data and methods strongly uphold previous suggestions that Acoelomorpha is sister clade to all other bilaterian animals, find diminishing evidence for the placement of the enigmatic Xenoturbella within Deuterostomia, and place Cycliophora with Entoprocta and Ectoprocta. The work highlights the implications that these arrangements have for metazoan evolution and permits a clearer picture of ancestral morphologies and life histories in the deep past.

Journal ArticleDOI
TL;DR: Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men, and after exclusion of all cancer cases during the first 3 years of the intervention.
Abstract: Summary Background Obesity is a risk factor for cancer. Intentional weight loss in the obese might protect against malignancy, but evidence is limited. To our knowledge, the Swedish Obese Subjects (SOS) study is the first intervention trial in the obese population to provide prospective, controlled cancer-incidence data. Methods The SOS study started in 1987 and involved 2010 obese patients (body-mass index [BMI] ≥34 kg/m 2 in men, and ≥38 kg/m 2 in women) who underwent bariatric surgery and 2037 contemporaneously matched obese controls, who received conventional treatment. While the main endpoint of SOS was overall mortality, the main outcome of this exploratory report was cancer incidence until Dec 31, 2005. Cancer follow-up rate was 99·9% and the median follow-up time was 10·9 years (range 0–18·1 years). Findings Bariatric surgery resulted in a sustained mean weight reduction of 19·9 kg (SD 15·6 kg) over 10 years, whereas the mean weight change in controls was a gain of 1·3 kg (SD 13·7 kg). The number of first-time cancers after inclusion was lower in the surgery group (n=117) than in the control group (n=169; HR 0·67, 95% CI 0·53–0·85, p=0·0009). The sex–treatment interaction p value was 0·054. In women, the number of first-time cancers after inclusion was lower in the surgery group (n=79) than in the control group (n=130; HR 0·58, 0·44–0·77; p=0·0001), whereas there was no effect of surgery in men (38 in the surgery group vs 39 in the control group; HR 0·97, 0·62–1·52; p=0·90). Similar results were obtained after exclusion of all cancer cases during the first 3 years of the intervention. Interpretation Bariatric surgery was associated with reduced cancer incidence in obese women but not in obese men. Funding Swedish Research Council, Swedish Foundation for Strategic Research, Swedish Federal Government under the LUA/ALF agreement, Hoffmann La Roche, Cederoths, AstraZeneca, Sanofi-Aventis, Ethicon Endosurgery.

Journal ArticleDOI
TL;DR: It is shown that the t(6;9)(q22–23;p23–24) translocation in adenoid cystic carcinomas of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB.
Abstract: The transcription factor gene MYB was identified recently as an oncogene that is rearranged/duplicated in some human leukemias. Here we describe a new mechanism of activation of MYB in human cancer involving gene fusion. We show that the t(6;9)(q22-23;p23-24) translocation in adenoid cystic carcinomas (ACC) of the breast and head and neck consistently results in fusions encoding chimeric transcripts predominantly consisting of MYB exon 14 linked to the last coding exon(s) of NFIB. The minimal common part of MYB deleted as the result of fusion was exon 15 including the 3'-UTR, which contains several highly conserved target sites for miR-15a/16 and miR-150 microRNAs. These microRNAs recently were shown to regulate MYB expression negatively. We suggest that deletion of these target sites may disrupt repression of MYB leading to overexpression of MYB-NFIB transcripts and protein and to activation of critical MYB targets, including genes associated with apoptosis, cell cycle control, cell growth/angiogenesis, and cell adhesion. Forced overexpression of miR-15a/16 and miR-150 in primary fusion-positive ACC cells did not significantly alter the expression of MYB as compared with leukemic cells with MYB activation/duplication. Our data indicate that the MYB-NFIB fusion is a hallmark of ACC and that deregulation of the expression of MYB and its target genes is a key oncogenic event in the pathogenesis of ACC. Our findings also suggest that the gain-of-function activity resulting from the MYB-NFIB fusion is a candidate therapeutic target.

Journal ArticleDOI
TL;DR: Primary efficacy outcomes in this phase 2 trial were not significant, and potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE ε4 carrier status.
Abstract: Background: Bapineuzumab, a humanized anti-amyloid-beta (Aβ) monoclonal antibody for the potential treatment of Alzheimer disease (AD), was evaluated in a multiple ascending dose, safety, and efficacy study in mild to moderate AD. Methods: The study enrolled 234 patients, randomly assigned to IV bapineuzumab or placebo in 4 dose cohorts (0.15, 0.5, 1.0, or 2.0 mg/kg). Patients received 6 infusions, 13 weeks apart, with final assessments at week 78. The prespecified primary efficacy analysis in the modified intent-to-treat population assumed linear decline and compared treatment differences within dose cohorts on the Alzheimer9s Disease Assessment Scale–Cognitive and Disability Assessment for Dementia. Exploratory analyses combined dose cohorts and did not assume a specific pattern of decline. Results: No significant differences were found in the primary efficacy analysis. Exploratory analyses showed potential treatment differences ( p APOE e4 noncarriers. Reversible vasogenic edema, detected on brain MRI in 12/124 (9.7%) bapineuzumab-treated patients, was more frequent in higher dose groups and APOE e4 carriers. Six vasogenic edema patients were asymptomatic; 6 experienced transient symptoms. Conclusions: Primary efficacy outcomes in this phase 2 trial were not significant. Potential treatment differences in the exploratory analyses support further investigation of bapineuzumab in phase 3 with special attention to APOE e4 carrier status. Classification of evidence: Due to varying doses and a lack of statistical precision, this Class II ascending dose trial provides insufficient evidence to support or refute a benefit of bapineuzumab.

Journal ArticleDOI
TL;DR: This paper attempts to summarize some ontogenetic and lifestyle traits that lead to an increased tolerance towards high environmental pCO2, and suggests that compensation of extracellular acid-base status in turn may be important in avoiding metabolic depression.
Abstract: . Future ocean acidification has the potential to adversely affect many marine organisms. A growing body of evidence suggests that many species could suffer from reduced fertilization success, decreases in larval- and adult growth rates, reduced calcification rates, and even mortality when being exposed to near-future levels (year 2100 scenarios) of ocean acidification. Little research focus is currently placed on those organisms/taxa that might be less vulnerable to the anticipated changes in ocean chemistry; this is unfortunate, as the comparison of more vulnerable to more tolerant physiotypes could provide us with those physiological traits that are crucial for ecological success in a future ocean. Here, we attempt to summarize some ontogenetic and lifestyle traits that lead to an increased tolerance towards high environmental pCO2. In general, marine ectothermic metazoans with an extensive extracellular fluid volume may be less vulnerable to future acidification as their cells are already exposed to much higher pCO2 values (0.1 to 0.4 kPa, ca. 1000 to 3900 μatm) than those of unicellular organisms and gametes, for which the ocean (0.04 kPa, ca. 400 μatm) is the extracellular space. A doubling in environmental pCO2 therefore only represents a 10% change in extracellular pCO2 in some marine teleosts. High extracellular pCO2 values are to some degree related to high metabolic rates, as diffusion gradients need to be high in order to excrete an amount of CO2 that is directly proportional to the amount of O2 consumed. In active metazoans, such as teleost fish, cephalopods and many brachyuran crustaceans, exercise induced increases in metabolic rate require an efficient ion-regulatory machinery for CO2 excretion and acid-base regulation, especially when anaerobic metabolism is involved and metabolic protons leak into the extracellular space. These ion-transport systems, which are located in highly developed gill epithelia, form the basis for efficient compensation of pH disturbances during exposure to elevated environmental pCO2. Compensation of extracellular acid-base status in turn may be important in avoiding metabolic depression. So far, maintained "performance" at higher seawater pCO2 (>0.3 to 0.6 kPa) has only been observed in adults/juveniles of active, high metabolic species with a powerful ion regulatory apparatus. However, while some of these taxa are adapted to cope with elevated pCO2 during their regular embryonic development, gametes, zygotes and early embryonic stages, which lack specialized ion-regulatory epithelia, may be the true bottleneck for ecological success – even of the more tolerant taxa. Our current understanding of which marine animal taxa will be affected adversely in their physiological and ecological fitness by projected scenarios of anthropogenic ocean acidification is quite incomplete. While a growing amount of empirical evidence from CO2 perturbation experiments suggests that several taxa might react quite sensitively to ocean acidification, others seem to be surprisingly tolerant. However, there is little mechanistic understanding on what physiological traits are responsible for the observed differential sensitivities (see reviews of Seibel and Walsh, 2003; Portner et al., 2004; Fabry et al., 2008; Portner, 2008). This leads us to the first very basic question of how to define general CO2 tolerance on the species level.

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TL;DR: In this paper, the first empirical orthogonal function (EOF) of observed summertime extratropical North Atlantic pressure at mean sea level is defined, which is characterized by a more northerly location and smaller spatial scale than its winter counterpart.
Abstract: Summer climate in the North Atlantic‐European sector possesses a principal pattern of year-to-year variability that is the parallel to the well-known North Atlantic Oscillation in winter. This summer North Atlantic Oscillation (SNAO) is defined here as the first empirical orthogonal function (EOF) of observed summertime extratropical North Atlantic pressure at mean sea level. It is shown to be characterized by a more northerly location and smaller spatial scale than its winter counterpart. The SNAO is also detected by cluster analysis and has a near-equivalent barotropic structure on daily and monthly time scales. Although of lesser amplitude than its wintertime counterpart, the SNAO exerts a strong influence on northern European rainfall, temperature, and cloudiness through changes in the position of the North Atlantic storm track. It is, therefore, of key importance in generating summer climate extremes, including flooding, drought, and heat

Journal ArticleDOI
TL;DR: Increased hygiene appears to have changed the gut flora of Western infants, which may affect the risk of developing immune mediated diseases.
Abstract: In adult individuals, the intestinal microbiota comprises several hundred, mostly anaerobic, bacterial species. This complex ecosystem is formed through the successive establishment of different bacteria in infancy and early childhood. Facultative and aerotolerant bacteria establish first, followed by more and more strict anaerobes. The bacteria derive from different sources and the colonization pattern is influenced by delivery mode and environmental factors. Commensal microbes provide the major drive for maturation of the immune system. Increased hygiene appears to have changed the gut flora of Western infants, which may affect the risk of developing immune mediated diseases. Conclusion: It is clear that the process of infant colonization needs to be studied further, since composition of the microbiota may impact on child health.

Journal ArticleDOI
Thorunn Rafnar1, Patrick Sulem1, Simon N. Stacey1, Frank Geller1, Julius Gudmundsson1, Asgeir Sigurdsson1, Margret Jakobsdottir1, Hafdis T. Helgadottir1, Steinunn Thorlacius1, Katja K H Aben2, Thorarinn Blondal1, Thorgeir E. Thorgeirsson1, Gudmar Thorleifsson1, Kristleifur Kristjansson1, Kristin Thorisdottir3, Rafn Ragnarsson, Bardur Sigurgeirsson3, Halla Skuladottir, Tomas Gudbjartsson3, Helgi J Isaksson, Gudmundur V. Einarsson, Kristrun R. Benediktsdottir3, Bjarni A. Agnarsson3, Karl Olafsson, Anna Salvarsdottir, Hjordis Bjarnason1, Margret Asgeirsdottir1, Kari T. Kristinsson1, Sigurborg Matthiasdottir1, Steinunn G Sveinsdottir, Silvia Polidoro4, Veronica Höiom5, Rafael Botella-Estrada, Kari Hemminki6, Peter Rudnai, D. Timothy Bishop7, Marcello Campagna8, Eliane Kellen9, Maurice P. Zeegers10, Maurice P. Zeegers11, Petra J. de Verdier5, Ana Ferrer12, Dolores Isla12, Maria Vidal12, Raquel Andrés12, Berta Saez, Pablo Juberías12, Javier Banzo12, Sebastian Navarrete12, Alejandro Tres12, Donghui Kan13, Annika Lindblom5, Eugene Gurzau, Kvetoslava Koppova, Femmie de Vegt14, Jack A. Schalken14, Henricus F. M. van der Heijden14, Hans J Smit, René A Termeer, Egbert Oosterwijk14, Onno van Hooij14, Eduardo Nagore, Stefano Porru8, Gunnar Steineck15, Gunnar Steineck5, Johan Hansson5, Frank Buntinx9, Frank Buntinx10, William J. Catalona13, Giuseppe Matullo4, Paolo Vineis16, Anne E. Kiltie7, Jose I. Mayordomo12, Rajesh Kumar6, Lambertus A. Kiemeney14, Michael L. Frigge1, Thorvaldur Jonsson3, Hafsteinn Saemundsson, Rosa B. Barkardottir, Eirikur Jonsson, Steinn Jonsson3, Jón Ólafsson3, Jeffrey R. Gulcher1, Gisli Masson1, Daniel F. Gudbjartsson1, Augustine Kong1, Unnur Thorsteinsdottir3, Unnur Thorsteinsdottir1, Kari Stefansson1, Kari Stefansson3 
TL;DR: It is found that rs401681[C] on chromosome 5p15 satisfied the threshold for genome-wide significance and seems to confer protection against cutaneous melanoma, and investigation of the region led to rs2736098[A], which showed stronger association with some cancer types, but neither variant could fully account for the association of the other.
Abstract: The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

Journal ArticleDOI
Lauren A. Weiss1, Lauren A. Weiss2, Dan E. Arking3, Mark J. Daly1  +211 moreInstitutions (54)
08 Oct 2009-Nature
TL;DR: A linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms in a common set of 1,031 multiplex autism families, implicating SEMA5A as an autism susceptibility gene.
Abstract: Although autism is a highly heritable neurodevelopmental disorder, attempts to identify specific susceptibility genes have thus far met with limited success. Genome-wide association studies using half a million or more markers, particularly those with very large sample sizes achieved through meta-analysis, have shown great success in mapping genes for other complex genetic traits. Consequently, we initiated a linkage and association mapping study using half a million genome-wide single nucleotide polymorphisms (SNPs) in a common set of 1,031 multiplex autism families (1,553 affected offspring). We identified regions of suggestive and significant linkage on chromosomes 6q27 and 20p13, respectively. Initial analysis did not yield genome-wide significant associations; however, genotyping of top hits in additional families revealed an SNP on chromosome 5p15 (between SEMA5A and TAS2R1) that was significantly associated with autism (P = 2 x 10(-7)). We also demonstrated that expression of SEMA5A is reduced in brains from autistic patients, further implicating SEMA5A as an autism susceptibility gene. The linkage regions reported here provide targets for rare variation screening whereas the discovery of a single novel association demonstrates the action of common variants.

Journal ArticleDOI
TL;DR: The results suggest that the Rubiaceae originated in the Paleotropics and used the boreotropical connection to reach South America, and the biogeographic patterns found corroborate the existence of a long-lasting dispersal barrier between the Northern and Central Andes, the “Western Andean Portal.”
Abstract: Recent phylogenetic studies have revealed the major role played by the uplift of the Andes in the extraordinary diversification of the Neotropical flora. These studies, however, have typically considered the Andean uplift as a single, time-limited event fostering the evolution of highland elements. This contrasts with geological reconstructions indicating that the uplift occurred in discrete periods from west to east and that it affected different regions at different times. We introduce an approach for integrating Andean tectonics with biogeographic reconstructions of Neotropical plants, using the coffee family (Rubiaceae) as a model group. The distribution of this family spans highland and montane habitats as well as tropical lowlands of Central and South America, thus offering a unique opportunity to study the influence of the Andean uplift on the entire Neotropical flora. Our results suggest that the Rubiaceae originated in the Paleotropics and used the boreotropical connection to reach South America. The biogeographic patterns found corroborate the existence of a long-lasting dispersal barrier between the Northern and Central Andes, the “Western Andean Portal.” The uplift of the Eastern Cordillera ended this barrier, allowing dispersal of boreotropical lineages to the South, but gave rise to a huge wetland system (“Lake Pebas”) in western Amazonia that prevented in situ speciation and floristic dispersal between the Andes and Amazonia for at least 6 million years. Here, we provide evidence of these events in plants.

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TL;DR: In this article, the authors reviewed two research programs focusing on variations in the number of women elected to national parliaments in the world (descriptive representation) and the second focusing on effects of women's presence in parliament (substantive representation).
Abstract: This essay reviews two research programs. The first focuses on variations in the number of women elected to national parliaments in the world (descriptive representation), and the second focuses on effects of women’s presence in parliament (substantive representation). The theory of the politics of presence (Phillips 1995) provides reasons for expecting a link between descriptive and substantive representation. The safest position would be to say that results are “mixed” when it comes to empirical support for the theory of the politics of presence. However, when a large number of studies covering a wide set of indicators on the importance of gender in the parliamentary process are piled together, the picture that emerges shows that female politicians contribute to strengthening the position of women’s interests.

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TL;DR: Choukroun's platelet-rich fibrin (PRF) is a second generation platelet concentrate that releases high quantities of three main growth factors, including TGFβ-1, platelet derived growth factor AB, PDGF-AB and an important coagulation matricellular glycoprotein during 7 days.
Abstract: Platelet concentrates for surgical topical applications are nowadays often used, but quantification of the long-term growth factor release from these preparations in most cases is impossible. Indeed, in most protocols, platelets are massively activated and there is no significant fibrin matrix to support growth factor release and cell migration. Choukroun's platelet-rich fibrin (PRF), a second generation platelet concentrate, is a leucocyte- and platelet-rich fibrin biomaterial. Here, we show that this dense fibrin membrane releases high quantities of three main growth factors (Transforming Growth Factor b-1 (TGFbeta-1), platelet derived growth factor AB, PDGF-AB; vascular endothelial growth factor, VEGF) and an important coagulation matricellular glycoprotein (thrombospondin-1, TSP-1) during 7 days. Moreover, the comparison between the final released amounts and the initial content of the membrane (after forcible extraction) allows us to consider that the leucocytes trapped in the fibrin matrix continue to produce high quantities of TGFbeta-1 and VEGF during the whole experimental time.

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TL;DR: It is proposed here that liver-derived circulating IGF-I and local bone-derived IGF- I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other (= redundancy) in the maintenance of normal longitudinal bone growth.
Abstract: IGF-I is expressed in virtually every tissue of the body, but with much higher expression in the liver than in any other tissue. Studies using mice with liver-specific IGF-I knockout have demonstrated that liver-derived IGF-I, constituting a major part of circulating IGF-I, is an important endocrine factor involved in a variety of physiological and pathological processes. Detailed studies comparing the impact of liver-derived IGF-I and local bone-derived IGF-I demonstrate that both sources of IGF-I can stimulate longitudinal bone growth. We propose here that liver-derived circulating IGF-I and local bone-derived IGF-I to some extent have overlapping growth-promoting effects and might have the capacity to replace each other (= redundancy) in the maintenance of normal longitudinal bone growth. Importantly, and in contrast to the regulation of longitudinal bone growth, locally derived IGF-I cannot replace (= lack of redundancy) liver-derived IGF-I for the regulation of a large number of other parameters including GH secretion, cortical bone mass, kidney size, prostate size, peripheral vascular resistance, spatial memory, sodium retention, insulin sensitivity, liver size, sexually dimorphic liver functions, and progression of some tumors. It is clear that a major role of liver-derived IGF-I is to regulate GH secretion and that some, but not all, of the phenotypes in the liver-specific IGF-I knockout mice are indirect, mediated via the elevated GH levels. All of the described multiple endocrine effects of liver-derived IGF-I should be considered in the development of possible novel treatment strategies aimed at increasing or reducing endocrine IGF-I activity.

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TL;DR: This article studied the impact of algorithmic trading in the foreign exchange market using a long time series of high-frequency data that identify computer-generated trading activity and found that the reduction in arbitrage opportunities is associated primarily with computers taking liquidity.
Abstract: We study the impact of algorithmic trading (AT) in the foreign exchange market using a long time series of high-frequency data that identify computer-generated trading activity. We find that AT causes an improvement in two measures of price efficiency: the frequency of triangular arbitrage opportunities and the autocorrelation of high-frequency returns. We show that the reduction in arbitrage opportunities is associated primarily with computers taking liquidity. This result is consistent with the view that AT improves informational efficiency by speeding up price discovery, but that it may also impose higher adverse selection costs on slower traders. In contrast, the reduction in the autocorrelation of returns owes more to the algorithmic provision of liquidity. We also find evidence consistent with the strategies of algorithmic traders being highly correlated. This correlation, however, does not appear to cause a degradation in market quality, at least not on average.

Posted Content
01 Jan 2009
TL;DR: In this article, the authors developed theoretical arguments and a statistical method that uses cross-industry labor flows to assess the skill-relatedness between industries and found that the resulting network that connects industries with overlapping skill requirements is highly predictive of diversification moves on the part of firms.
Abstract: According to the knowledge-based view of the firm, a firm’s workforce is its most important resource, and firms often diversify into activities that allow them to leverage human resources. Human capital also represents a main asset for employees. When switching jobs, individuals are expected to remain in industries that value the skills that they have developed in their previous work. Based on this observation, this article develops theoretical arguments and a statistical method that uses cross-industry labor flows to assess the skill-relatedness between industries. Industries classified in different sectors of the economy sometimes exhibit strong skill-relatedness linkages. Also, industry space, i.e., the resulting network that connects industries with overlapping skill requirements, is highly predictive of diversification moves on the part of firms. Diversification is found to be over 100 times more likely to occur into industries that have ties to a firm’s core activity in terms of skills than into industries that do not. This effect of skill-relatedness eclipses the effect of other types of relatedness, such as value chain linkages and classification-based relatedness.

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TL;DR: In very well-trained 70-year-old men high levels of oxidative enzymes are found together with high maximal aerobic power capacity, which can be increased by physical training also in the elderly.
Abstract: Most elderly people have some kind of regular daily activity, usually closely connected to their daily habits. A six-graded scale for classification of physical activity is presented. Persons with a low physical activity also usually perceive their physical strain as rather light or moderate. There is a reduction with age in muscle volume, muscle strength, and aerobic capacity which are rather parallel. From a muscular point of view there are only moderate qualitative changes up to the ages around 70; at higher ages there will be a tendency to more marked changes in muscle structure. The maximal aerobic power as well as muscle strength can be increased by physical training also in the elderly. At least up to the ages around 70 there will be an adaptation in muscle structure and enzymatic capacity. In very well-trained 70-year-old men high levels of oxidative enzymes are found together with high maximal aerobic power capacity. A positive attitude should be taken towards physical exercise for prevention and rehabilitation also in the elderly.