Showing papers by "University of Bonn published in 2010"

A Draft Sequence of the Neandertal Genome

Abstract: Neandertals, the closest evolutionary relatives of present-day humans, lived in large parts of Europe and western Asia before disappearing 30,000 years ago. We present a draft sequence of the Neandertal genome composed of more than 4 billion nucleotides from three individuals. Comparisons of the Neandertal genome to the genomes of five present-day humans from different parts of the world identify a number of genomic regions that may have been affected by positive selection in ancestral modern humans, including genes involved in metabolism and in cognitive and skeletal development. We show that Neandertals shared more genetic variants with present-day humans in Eurasia than with present-day humans in sub-Saharan Africa, suggesting that gene flow from Neandertals into the ancestors of non-Africans occurred before the divergence of Eurasian groups from each other.

NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals

Abstract: The inflammatory nature of atherosclerosis is well established but the agent(s) that incite inflammation in the artery wall remain largely unknown. Germ-free animals are susceptible to atherosclerosis, suggesting that endogenous substances initiate the inflammation. Mature atherosclerotic lesions contain macroscopic deposits of cholesterol crystals in the necrotic core, but their appearance late in atherogenesis had been thought to disqualify them as primary inflammatory stimuli. However, using a new microscopic technique, we revealed that minute cholesterol crystals are present in early diet-induced atherosclerotic lesions and that their appearance in mice coincides with the first appearance of inflammatory cells. Other crystalline substances can induce inflammation by stimulating the caspase-1-activating NLRP3 (NALP3 or cryopyrin) inflammasome, which results in cleavage and secretion of interleukin (IL)-1 family cytokines. Here we show that cholesterol crystals activate the NLRP3 inflammasome in phagocytes in vitro in a process that involves phagolysosomal damage. Similarly, when injected intraperitoneally, cholesterol crystals induce acute inflammation, which is impaired in mice deficient in components of the NLRP3 inflammasome, cathepsin B, cathepsin L or IL-1 molecules. Moreover, when mice deficient in low-density lipoprotein receptor (LDLR) were bone-marrow transplanted with NLRP3-deficient, ASC (also known as PYCARD)-deficient or IL-1alpha/beta-deficient bone marrow and fed on a high-cholesterol diet, they had markedly decreased early atherosclerosis and inflammasome-dependent IL-18 levels. Minimally modified LDL can lead to cholesterol crystallization concomitant with NLRP3 inflammasome priming and activation in macrophages. Although there is the possibility that oxidized LDL activates the NLRP3 inflammasome in vivo, our results demonstrate that crystalline cholesterol acts as an endogenous danger signal and its deposition in arteries or elsewhere is an early cause rather than a late consequence of inflammation. These findings provide new insights into the pathogenesis of atherosclerosis and indicate new potential molecular targets for the therapy of this disease.

Review of Particle Physics

Abstract: This biennial Review summarizes much of particle physics. Using data from previous editions, plus 2158 new measurements from 551 papers, we list, evaluate, and average measured properties of gauge bosons, leptons, quarks, mesons, and baryons. We also summarize searches for hypothetical particles such as Higgs bosons, heavy neutrinos, and supersymmetric particles. All the particle properties and search limits are listed in Summary Tables. We also give numerous tables, figures, formulae, and reviews of topics such as the Standard Model, particle detectors, probability, and statistics. Among the 108 reviews are many that are new or heavily revised including those on neutrino mass, mixing, and oscillations, QCD, top quark, CKM quark-mixing matrix, V-ud & V-us, V-cb & V-ub, fragmentation functions, particle detectors for accelerator and non-accelerator physics, magnetic monopoles, cosmological parameters, and big bang cosmology.

The ATLAS Simulation Infrastructure

Abstract: The simulation software for the ATLAS Experiment at the Large Hadron Collider is being used for large-scale production of events on the LHC Computing Grid. This simulation requires many components, from the generators that simulate particle collisions, through packages simulating the response of the various detectors and triggers. All of these components come together under the ATLAS simulation infrastructure. In this paper, that infrastructure is discussed, including that supporting the detector description, interfacing the event generation, and combining the GEANT4 simulation of the response of the individual detectors. Also described are the tools allowing the software validation, performance testing, and the validation of the simulated output against known physics processes.

Precipitation downscaling under climate change: Recent developments to bridge the gap between dynamical models and the end user

Abstract: Precipitation downscaling improves the coarse resolution and poor representation of precipitation in global climate models and helps end users to assess the likely hydrological impacts of climate change. This paper integrates perspectives from meteorologists, climatologists, statisticians, and hydrologists to identify generic end user (in particular, impact modeler) needs and to discuss downscaling capabilities and gaps. End users need a reliable representation of precipitation intensities and temporal and spatial variability, as well as physical consistency, independent of region and season. In addition to presenting dynamical downscaling, we review perfect prognosis statistical downscaling, model output statistics, and weather generators, focusing on recent developments to improve the representation of space-time variability. Furthermore, evaluation techniques to assess downscaling skill are presented. Downscaling adds considerable value to projections from global climate models. Remaining gaps are uncertainties arising from sparse data; representation of extreme summer precipitation, subdaily precipitation, and full precipitation fields on fine scales; capturing changes in small-scale processes and their feedback on large scales; and errors inherited from the driving global climate model.

IFI16 is an innate immune sensor for intracellular DNA.

Abstract: The detection of intracellular microbial DNA is critical to appropriate innate immune responses; however, knowledge of how such DNA is sensed is limited. Here we identify IFI16, a PYHIN protein, as an intracellular DNA sensor that mediates the induction of interferon-β (IFN-β). IFI16 directly associated with IFN-β-inducing viral DNA motifs. STING, a critical mediator of IFN-β responses to DNA, was recruited to IFI16 after DNA stimulation. Lowering the expression of IFI16 or its mouse ortholog p204 by RNA-mediated interference inhibited gene induction and activation of the transcription factors IRF3 and NF-κB induced by DNA and herpes simplex virus type 1 (HSV-1). IFI16 (p204) is the first PYHIN protein to our knowledge shown to be involved in IFN-β induction. Thus, the PYHIN proteins IFI16 and AIM2 form a new family of innate DNA sensors we call 'AIM2-like receptors' (ALRs).

SPECTRA AND HUBBLE SPACE TELESCOPE LIGHT CURVES OF SIX TYPE Ia SUPERNOVAE AT 0.511 <z< 1.12 AND THE UNION2 COMPILATION ∗

Abstract: We report on work to increase the number of well-measured Type Ia supernovae (SNe Ia) at high redshifts. Light curves, including high signal-to-noise HST data, and spectra of six SNe Ia that were discovered during 2001 are presented. Additionally, for the two SNe with z > 1, we present groundbased J-band photometry from Gemini and the VLT. These are among the most distant SNe Ia for which ground based near-IR observations have been obtained. We add these six SNe Ia together with other data sets that have recently become available in the literature to the Union compilation (Kowalski et al. 2008). We have made a number of refinements to the Union analysis chain, the most important ones being the refitting of all light curves with the SALT2 fitter and an improved handling of systematic errors. We call this new compilation, consisting of 557 supernovae, the Union2

Evaluation of pooling operations in convolutional architectures for object recognition

Abstract: A common practice to gain invariant features in object recognition models is to aggregate multiple low-level features over a small neighborhood. However, the differences between those models makes a comparison of the properties of different aggregation functions hard. Our aim is to gain insight into different functions by directly comparing them on a fixed architecture for several common object recognition tasks. Empirical results show that a maximum pooling operation significantly outperforms subsampling operations. Despite their shift-invariant properties, overlapping pooling windows are no significant improvement over nonoverlapping pooling windows. By applying this knowledge, we achieve state-of-the-art error rates of 4.57% on the NORB normalized-uniform dataset and 5.6% on the NORB jittered-cluttered dataset.

Groundwater use for irrigation - a global inventory

Abstract: . Irrigation is the most important water use sector accounting for about 70% of the global freshwater withdrawals and 90% of consumptive water uses. While the extent of irrigation and related water uses are reported in statistical databases or estimated by model simulations, information on the source of irrigation water is scarce and very scattered. Here we present a new global inventory on the extent of areas irrigated with groundwater, surface water or non-conventional sources, and we determine the related consumptive water uses. The inventory provides data for 15 038 national and sub-national administrative units. Irrigated area was provided by census-based statistics from international and national organizations. A global model was then applied to simulate consumptive water uses for irrigation by water source. Globally, area equipped for irrigation is currently about 301 million ha of which 38% are equipped for irrigation with groundwater. Total consumptive groundwater use for irrigation is estimated as 545 km3 yr−1, or 43% of the total consumptive irrigation water use of 1277 km3 yr−1. The countries with the largest extent of areas equipped for irrigation with groundwater, in absolute terms, are India (39 million ha), China (19 million ha) and the USA (17 million ha). Groundwater use in irrigation is increasing both in absolute terms and in percentage of total irrigation, leading in places to concentrations of users exploiting groundwater storage at rates above groundwater recharge. Despite the uncertainties associated with statistical data available to track patterns and growth of groundwater use for irrigation, the inventory presented here is a major step towards a more informed assessment of agricultural water use and its consequences for the global water cycle.

TreeGraph 2: Combining and visualizing evidence from different phylogenetic analyses

Abstract: Today it is common to apply multiple potentially conflicting data sources to a given phylogenetic problem. At the same time, several different inference techniques are routinely employed instead of relying on just one. In view of both trends it is becoming increasingly important to be able to efficiently compare different sets of statistical values supporting (or conflicting with) the nodes of a given tree topology, and merging this into a meaningful representation. A tree editor supporting this should also allow for flexible editing operations and be able to produce ready-to-publish figures. We developed TreeGraph 2, a GUI-based graphical editor for phylogenetic trees (available from http://treegraph.bioinfweb.info ). It allows automatically combining information from different phylogenetic analyses of a given dataset (or from different subsets of the dataset), and helps to identify and graphically present incongruences. The program features versatile editing and formatting options, such as automatically setting line widths or colors according to the value of any of the unlimited number of variables that can be assigned to each node or branch. These node/branch data can be imported from spread sheets or other trees, be calculated from each other by specified mathematical expressions, filtered, copied from and to other internal variables, be kept invisible or set visible and then be freely formatted (individually or across the whole tree). Beyond typical editing operations such as tree rerooting and ladderizing or moving and collapsing of nodes, whole clades can be copied from other files and be inserted (along with all node/branch data and legends), but can also be manually added and, thus, whole trees can quickly be manually constructed de novo. TreeGraph 2 outputs various graphic formats such as SVG, PDF, or PNG, useful for tree figures in both publications and presentations. TreeGraph 2 is a user-friendly, fully documented application to produce ready-to-publish trees. It can display any number of annotations in several ways, and permits easily importing and combining them. Additionally, a great number of editing- and formatting-operations is available.

MIRCA2000—Global monthly irrigated and rainfed crop areas around the year 2000: A new high‐resolution data set for agricultural and hydrological modeling

Abstract: [1] To support global-scale assessments that are sensitive to agricultural land use, we developed the global data set of monthly irrigated and rainfed crop areas around the year 2000 (MIRCA2000). With a spatial resolution of 5 arc min (about 9.2 km at the equator), MIRCA2000 provides both irrigated and rainfed crop areas of 26 crop classes for each month of the year. The data set covers all major food crops as well as cotton. Other crops are grouped into categories (perennial, annual, and fodder grasses). It represents multicropping systems and maximizes consistency with census-based national and subnational statistics. According to MIRCA2000, 25% of the global harvested areas are irrigated, with a cropping intensity (including fallow land) of 1.12, as compared to 0.84 for the sum of rainfed and irrigated harvested crops. For the dominant crops (rice (1.7 million km2 harvested area), wheat (2.1 million km2), and maize (1.5 million km2)), roughly 60%, 30%, and 20% of the harvested areas are irrigated, respectively, and half of the citrus, sugar cane, and cotton areas. While wheat and maize are the crops with the largest rainfed harvested areas (1.5 million km2 and 1.2 million km2, respectively), rice is clearly the crop with the largest irrigated harvested area (1.0 million km2), followed by wheat (0.7 million km2) and maize (0.3 million km2). Using MIRCA2000, 33% of global crop production and 44% of total cereal production were determined to come from irrigated agriculture.

The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses.

Abstract: Inflammasomes regulate the activity of caspase-1 and the maturation of interleukin 1 (IL-1) and IL-18. AIM2 has been shown to bind DNA and engage the caspase-1-activating adaptor protein ASC to form a caspase-1-activating inflammasome. Using Aim2-deficient mice, we identify a central role for AIM2 in regulating caspase-1-dependent maturation of IL-1 and IL-18, as well as pyroptosis, in response to synthetic double-stranded DNA. AIM2 was essential for inflammasome activation in response to Francisella tularensis, vaccinia virus and mouse cytomegalovirus and had a partial role in the sensing of Listeria monocytogenes. Moreover, production of IL-18 and natural killer cell–dependent production of interferon-, events critical in the early control of virus replication, were dependent on AIM2 during mouse cytomegalovirus infection in vivo. Collectively, our observations demonstrate the importance of AIM2 in the sensing of both bacterial and viral pathogens and in triggering innate immunity. A r t i c l e s

Anthropogenic transformation of the biomes, 1700 to 2000

Abstract: Aim To map and characterize anthropogenic transformation of the terrestrial biosphere before and during the Industrial Revolution, from 1700 to 2000. Location Global. Methods Anthropogenic biomes (anthromes) were mapped for 1700, 1800, 1900 and 2000 using a rule-based anthrome classification model applied to gridded global data for human population density and land use. Anthropogenic transformation of terrestrial biomes was then characterized by map comparisons at century intervals. Results In 1700, nearly half of the terrestrial biosphere was wild, without human settlements or substantial land use. Most of the remainder was in a seminatural state (45%) having only minor use for agriculture and settlements. By 2000, the opposite was true, with the majority of the biosphere in agricultural and settled anthromes, less than 20% seminatural and only a quarter left wild. Anthropogenic transformation of the biosphere during the Industrial Revolution resulted about equally from land-use expansion into wildlands and intensification of land use within seminatural anthromes. Transformation pathways differed strongly between biomes and regions, with some remaining mostly wild but with the majority almost completely transformed into rangelands, croplands and villages. In the process of transforming almost 39% of earth's total ice-free surface into agricultural land and settlements, an additional 37% of global land without such use has become embedded within agricultural and settled anthromes. Main conclusions Between 1700 and 2000, the terrestrial biosphere made the critical transition from mostly wild to mostly anthropogenic, passing the 50% mark early in the 20th century. At present, and ever more in the future, the form and process of terrestrial ecosystems in most biomes will be predominantly anthropogenic, the product of land use and other direct human interactions with ecosystems. Ecological research and conservation efforts in all but a few biomes would benefit from a primary focus on the novel remnant, recovering and managed ecosystems embedded within used lands.

Early Use of TIPS in Patients with Cirrhosis and Variceal Bleeding

Abstract: Background Patients with cirrhosis in Child–Pugh class C or those in class B who have persistent bleeding at endoscopy are at high risk for treatment failure and a poor prognosis, even if they have undergone rescue treatment with a transjugular intrahepatic portosystemic shunt (TIPS). This study evaluated the earlier use of TIPS in such patients. Methods We randomly assigned, within 24 hours after admission, a total of 63 patients with cirrhosis and acute variceal bleeding who had been treated with vasoactive drugs plus endoscopic therapy to treatment with a polytetrafluoroethylene-covered stent within 72 hours after randomization (early-TIPS group, 32 patients) or continuation of vasoactive-drug therapy, followed after 3 to 5 days by treatment with propranolol or nadolol and long-term endoscopic band ligation (EBL), with insertion of a TIPS if needed as rescue therapy (pharmacotherapy–EBL group, 31 patients). Results During a median follow-up of 16 months, rebleeding or failure to control bleeding occurr...

N-methyl-d-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes

Abstract: Antibodies to the N-methyl-d-aspartate subtype of glutamate receptor have been associated with a newly-described encephalopathy that has been mainly identified in young females with ovarian tumours. However, the full clinical spectrum and treatment responses are not yet clear. We established a sensitive cell-based assay for detection of N-methyl-d-aspartate receptor antibodies in serum or cerebrospinal fluid, and a quantitative fluorescent immunoprecipitation assay for serial studies. Although there was marked intrathecal synthesis of N-methyl-d-aspartate receptor antibodies, the absolute levels of N-methyl-d-aspartate receptor antibodies were higher in serum than in cerebrospinal fluid. N-methyl-d-aspartate receptor antibodies were of the immunoglobulin G1 subclass and were able to activate complement on N-methyl d-aspartate receptor-expressing human embryonic kidney cells. From questionnaires returned on 44 N-methyl-d-aspartate receptor antibody-positive patients, we identified a high proportion without a detected tumour (35/44, 80%: follow-up 3.6–121 months, median 16 months). Among the latter were 15 adult females (43%), 10 adult males (29%) and 10 children (29%), with four in the first decade of life. Overall, there was a high proportion (29%) of non-Caucasians. Good clinical outcomes, as defined by reductions in modified Rankin scores, correlated with decreased N-methyl-d-aspartate receptor antibody levels and were associated with early (<40 days) administration of immunotherapies in non-paraneoplastic patients (P < 0.0001) and earlier tumour removal in paraneoplastic patients (P = 0.02). Ten patients (23%) who were first diagnosed during relapses had no evidence of tumours but had received minimal or no immunotherapy during earlier episodes. Temporal analysis of the onset of the neurological features suggested progression through two main stages. The time of onset of the early features, characterized by neuropsychiatric symptoms and seizures preceded by a median of 10–20 days, the onset of movement disorders, reduction in consciousness and dysautonomia. This temporal dichotomy was also seen in the timing of cerebrospinal fluid, electroencephalographic and in the rather infrequent cerebral imaging changes. Overall, our data support a model in which the early features are associated with cerebrospinal fluid lymphocytosis, and the later features with appearance of oligoclonal bands. The immunological events and neuronal mechanisms underlying these observations need to be explored further, but one possibility is that the early stage represents diffusion of serum antibodies into the cortical grey matter, whereas the later stage results from secondary expansion of the immunological repertoire within the intrathecal compartment acting on subcortical neurons. Four patients, who only had temporal lobe epilepsy without oligoclonal bands, may represent restriction to the first stage.

Frequent and Focal FGFR1 Amplification Associates with Therapeutically Tractable FGFR1 Dependency in Squamous Cell Lung Cancer

Abstract: Lung cancer remains one of the leading causes of cancer-related death in developed countries. Although lung adenocarcinomas with EGFR mutations or EML4-ALK fusions respond to treatment by epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) inhibition, respectively, squamous cell lung cancer currently lacks therapeutically exploitable genetic alterations. We conducted a systematic search in a set of 232 lung cancer specimens for genetic alterations that were therapeutically amenable and then performed high-resolution gene copy number analyses. We identified frequent and focal fibroblast growth factor receptor 1 (FGFR1) amplification in squamous cell lung cancer (n = 155), but not in other lung cancer subtypes, and, by fluorescence in situ hybridization, confirmed the presence of FGFR1 amplifications in an independent cohort of squamous cell lung cancer samples (22% of cases). Using cell-based screening with the FGFR inhibitor PD173074 in a large (n = 83) panel of lung cancer cell lines, we demonstrated that this compound inhibited growth and induced apoptosis specifically in those lung cancer cells carrying amplified FGFR1. We validated the FGFR1 dependence of FGFR1-amplified cell lines by FGFR1 knockdown and by ectopic expression of an FGFR1-resistant allele (FGFR1(V561M)), which rescued FGFR1-amplified cells from PD173074-mediated cytotoxicity. Finally, we showed that inhibition of FGFR1 with a small molecule led to significant tumor shrinkage in vivo. Thus, focal FGFR1 amplification is common in squamous cell lung cancer and associated with tumor growth and survival, suggesting that FGFR inhibitors may be a viable therapeutic option in this cohort of patients.

Cross-frequency coupling supports multi-item working memory in the human hippocampus

Abstract: Recent findings indicate that the hippocampus supports not only long-term memory encoding but also plays a role in working memory (WM) maintenance of multiple items; however, the neural mechanism underlying multi-item maintenance is still unclear. Theoretical work suggests that multiple items are being maintained by neural assemblies synchronized in the gamma frequency range (25–100 Hz) that are locked to consecutive phase ranges of oscillatory activity in the theta frequency range (4–8 Hz). Indeed, cross-frequency coupling of the amplitude of high-frequency activity to the phase of slower oscillations has been described both in animals and in humans, but has never been linked to a theoretical model of a cognitive process. Here we used intracranial EEG recordings in human epilepsy patients to test pivotal predictions from theoretical work. First, we show that simultaneous maintenance of multiple items in WM is accompanied by cross-frequency coupling of oscillatory activity in the hippocampus, which is recruited during multi-item WM. Second, maintenance of an increasing number of items is associated with modulation of beta/gamma amplitude with theta band activity of lower frequency, consistent with the idea that longer cycles are required for an increased number of representations by gamma cycles. This effect cannot be explained by a difference in theta or beta/gamma power. Third, we describe how the precision of cross-frequency coupling predicts individual WM performance. These data support the idea that working memory in humans depends on a neural code using phase information.

PGC-1α, A Potential Therapeutic Target for Early Intervention in Parkinson’s Disease

Abstract: Parkinson’s disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson’s and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson’s disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator–activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson’s disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson’s disease identifies PGC-1α as a potential therapeutic target for early intervention.

Morphological Attribute Profiles for the Analysis of Very High Resolution Images

Abstract: Morphological attribute profiles (APs) are defined as a generalization of the recently proposed morphological profiles (MPs). APs provide a multilevel characterization of an image created by the sequential application of morphological attribute filters that can be used to model different kinds of the structural information. According to the type of the attributes considered in the morphological attribute transformation, different parametric features can be modeled. The generation of APs, thanks to an efficient implementation, strongly reduces the computational load required for the computation of conventional MPs. Moreover, the characterization of the image with different attributes leads to a more complete description of the scene and to a more accurate modeling of the spatial information than with the use of conventional morphological filters based on a predefined structuring element. Here, the features extracted by the proposed operators were used for the classification of two very high resolution panchromatic images acquired by Quickbird on the city of Trento, Italy. The experimental analysis proved the usefulness of APs in modeling the spatial information present in the images. The classification maps obtained by considering different APs result in a better description of the scene (both in terms of thematic and geometric accuracy) than those obtained with an MP.

Patients with IDH1 wild type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: Implications for classification of gliomas

Abstract: WHO grading of human brain tumors extends beyond a strictly histological grading system by providing a basis predictive for the clinical behavior of the respective neoplasm. For example, patients with glioblastoma WHO grade IV usually show a less favorable clinical course and receive more aggressive first-line treatment than patients with anaplastic astrocytoma WHO grade III. Here we provide evidence that the IDH1 status is more prognostic for overall survival than standard histological criteria that differentiate high-grade astrocytomas. We sequenced the isocitrate dehydrogenase 1 gene (IDH1) at codon 132 in 382 patients with anaplastic astrocytoma and glioblastoma from the NOA-04 trial and from a prospective translational cohort study of the German Glioma Network. Patients with anaplastic astrocytomas carried IDH1 mutations in 60%, and patients with glioblastomas in 7.2%. IDH1 was the most prominent single prognostic factor (RR 2.7; 95% CI 1.6–4.5) followed by age, diagnosis and MGMT. The sequence from more favorable to poorer outcome was (1) anaplastic astrocytoma with IDH1 mutation, (2) glioblastoma with IDH1 mutation, (3) anaplastic astrocytoma without IDH1 mutation and (4) glioblastoma without IDH1 mutation (p < 0.0001). In this combined set of anaplastic astrocytomas and glioblastomas both, IDH1 mutation and IDH1 expression status were of greater prognostic relevance than histological diagnosis according to the current WHO classification system. Our data indicate that much of the prognostic significance of patient age is due to the predominant occurrence of IDH1 mutations in younger patients. Immunohistochemistry using a mutation-specific antibody recognizing the R132H mutation yielded similar results. We propose to complement the current WHO classification and grading of high-grade astrocytic gliomas by the IDH1 mutation status and to use this combined histological and molecular classification in future clinical trials.

Oxytocin Enhances Amygdala-Dependent, Socially Reinforced Learning and Emotional Empathy in Humans

Abstract: Oxytocin (OT) is becoming increasingly established as a prosocial neuropeptide in humans with therapeutic potential in treatment of social, cognitive, and mood disorders. However, the potential of OT as a general facilitator of human learning and empathy is unclear. The current double-blind experiments on healthy adult male volunteers investigated first whether treatment with intranasal OT enhanced learning performance on a feedback-guided item-category association task where either social (smiling and angry faces) or nonsocial (green and red lights) reinforcers were used, and second whether it increased either cognitive or emotional empathy measured by the Multifaceted Empathy Test. Further experiments investigated whether OT-sensitive behavioral components required a normal functional amygdala. Results in control groups showed that learning performance was improved when social rather than nonsocial reinforcement was used. Intranasal OT potentiated this social reinforcement advantage and greatly increased emotional, but not cognitive, empathy in response to both positive and negative valence stimuli. Interestingly, after OT treatment, emotional empathy responses in men were raised to levels similar to those found in untreated women. Two patients with selective bilateral damage to the amygdala (monozygotic twins with congenital Urbach-Wiethe disease) were impaired on both OT-sensitive aspects of these learning and empathy tasks, but performed normally on nonsocially reinforced learning and cognitive empathy. Overall these findings provide the first demonstration that OT can facilitate amygdala-dependent, socially reinforced learning and emotional empathy in men.

Bose–Einstein condensation of photons in an optical microcavity

Abstract: Bose–Einstein condensation has been observed in several physical systems, but is not predicted to occur for blackbody radiation such as photons. However, it becomes theoretically possible in the presence of thermalization processes that conserve photon number. Martin Weitz and colleagues have now realized such conditions experimentally, observing Bose–Einstein condensation of photons in a dye-filled optical microcavity. The effect is of interest for fundamental studies and may lead to new coherent ultraviolet sources. Bose–Einstein condensation has been observed in several physical systems, but is not predicted to occur for blackbody radiation such as photons. However, it becomes theoretically possible in the presence of thermalization processes that conserve photon number. These authors experimentally realise such conditions, observing Bose–Einstein condensation of photons in a dye-filled optical microcavity. The effect is of interest for fundamental studies and may lead to new coherent ultraviolet sources. Bose–Einstein condensation (BEC)—the macroscopic ground-state accumulation of particles with integer spin (bosons) at low temperature and high density—has been observed in several physical systems1,2,3,4,5,6,7,8,9, including cold atomic gases and solid-state quasiparticles. However, the most omnipresent Bose gas, blackbody radiation (radiation in thermal equilibrium with the cavity walls) does not show this phase transition. In such systems photons have a vanishing chemical potential, meaning that their number is not conserved when the temperature of the photon gas is varied10; at low temperatures, photons disappear in the cavity walls instead of occupying the cavity ground state. Theoretical works have considered thermalization processes that conserve photon number (a prerequisite for BEC), involving Compton scattering with a gas of thermal electrons11 or photon–photon scattering in a nonlinear resonator configuration12,13. Number-conserving thermalization was experimentally observed14 for a two-dimensional photon gas in a dye-filled optical microcavity, which acts as a ‘white-wall’ box. Here we report the observation of a Bose–Einstein condensate of photons in this system. The cavity mirrors provide both a confining potential and a non-vanishing effective photon mass, making the system formally equivalent to a two-dimensional gas of trapped, massive bosons. The photons thermalize to the temperature of the dye solution (room temperature) by multiple scattering with the dye molecules. Upon increasing the photon density, we observe the following BEC signatures: the photon energies have a Bose–Einstein distribution with a massively populated ground-state mode on top of a broad thermal wing; the phase transition occurs at the expected photon density and exhibits the predicted dependence on cavity geometry; and the ground-state mode emerges even for a spatially displaced pump spot. The prospects of the observed effects include studies of extremely weakly interacting low-dimensional Bose gases9 and new coherent ultraviolet sources15.

Observation of a centrality-dependent dijet asymmetry in lead-lead collisions at √sNN=2.76 Tev with the ATLAS detector at the LHC

Abstract: By using the ATLAS detector, observations have been made of a centrality-dependent dijet asymmetry in the collisions of lead ions at the Large Hadron Collider. In a sample of lead-lead events with a per-nucleon center of mass energy of 2.76 TeV, selected with a minimum bias trigger, jets are reconstructed in fine-grained, longitudinally segmented electromagnetic and hadronic calorimeters. The transverse energies of dijets in opposite hemispheres are observed to become systematically more unbalanced with increasing event centrality leading to a large number of events which contain highly asymmetric dijets. This is the first observation of an enhancement of events with such large dijet asymmetries, not observed in proton-proton collisions, which may point to an interpretation in terms of strong jet energy loss in a hot, dense medium.

Combined Measurement and QCD Analysis of the Inclusive e± p Scattering Cross Sections at HERA

Abstract: A combination is presented of the inclusive deep inelastic cross sections measured by the H1 and ZEUS Collaborations in neutral and charged current unpolarised e(+/-)p scattering at HERA during the period 1994-2000. The data span six orders of magnitude in negative four-momentum-transfer squared, Q(2), and in Bjorken x. The combination method used takes the correlations of systematic uncertainties into account, resulting in an improved accuracy. The combined data are the sole input in a NLO QCD analysis which determines a new set of parton distributions, HERAPDF1.0, with small experimental uncertainties. This set includes an estimate of the model and parametrisation uncertainties of the fit result.

Genetic evidence implicates the immune system and cholesterol metabolism in the aetiology of Alzheimer's disease.

Abstract: Background 1Late Onset Alzheimer's disease (LOAD) is the leading cause of dementia. Recent large genome-wide association studies (GWAS) identified the first strongly supported LOAD susceptibility genes since the discovery of the involvement of APOE in the early 1990s. We have now exploited these GWAS datasets to uncover key LOAD pathophysiological processes. Methodology We applied a recently developed tool for mining GWAS data for biologically meaningful information to a LOAD GWAS dataset. The principal findings were then tested in an independent GWAS dataset. Principal Findings We found a significant overrepresentation of association signals in pathways related to cholesterol metabolism and the immune response in both of the two largest genome-wide association studies for LOAD. Significance Processes related to cholesterol metabolism and the innate immune response have previously been implicated by pathological and epidemiological studies of Alzheimer's disease, but it has been unclear whether those findings reflected primary aetiological events or consequences of the disease process. Our independent evidence from two large studies now demonstrates that these processes are aetiologically relevant, and suggests that they may be suitable targets for novel and existing therapeutic approaches.

Biomarkers for Alzheimer's disease: academic, industry and regulatory perspectives

Abstract: Advances in therapeutic strategies for Alzheimer's disease that lead to even small delays in onset and progression of the condition would significantly reduce the global burden of the disease To effectively test compounds for Alzheimer's disease and bring therapy to individuals as early as possible there is an urgent need for collaboration between academic institutions, industry and regulatory organizations for the establishment of standards and networks for the identification and qualification of biological marker candidates Biomarkers are needed to monitor drug safety, to identify individuals who are most likely to respond to specific treatments, to stratify presymptomatic patients and to quantify the benefits of treatments Biomarkers that achieve these characteristics should enable objective business decisions in portfolio management and facilitate regulatory approval of new therapies

The Herschel ATLAS

Abstract: The Herschel ATLAS is the largest open-time key project that will be carried out on the Herschel Space Observatory. It will survey 570 deg2 of the extragalactic sky, 4 times larger than all the other Herschel extragalactic surveys combined, in five far-infrared and submillimeter bands. We describe the survey, the complementary multiwavelength data sets that will be combined with the Herschel data, and the six major science programs we are undertaking. Using new models based on a previous submillimeter survey of galaxies, we present predictions of the properties of the ATLAS sources in other wave bands.