Showing papers by "University of Freiburg published in 2012"

Guidelines for the use and interpretation of assays for monitoring autophagy

Abstract: In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

A benchmark for the evaluation of RGB-D SLAM systems

Abstract: In this paper, we present a novel benchmark for the evaluation of RGB-D SLAM systems. We recorded a large set of image sequences from a Microsoft Kinect with highly accurate and time-synchronized ground truth camera poses from a motion capture system. The sequences contain both the color and depth images in full sensor resolution (640 × 480) at video frame rate (30 Hz). The ground-truth trajectory was obtained from a motion-capture system with eight high-speed tracking cameras (100 Hz). The dataset consists of 39 sequences that were recorded in an office environment and an industrial hall. The dataset covers a large variety of scenes and camera motions. We provide sequences for debugging with slow motions as well as longer trajectories with and without loop closures. Most sequences were recorded from a handheld Kinect with unconstrained 6-DOF motions but we also provide sequences from a Kinect mounted on a Pioneer 3 robot that was manually navigated through a cluttered indoor environment. To stimulate the comparison of different approaches, we provide automatic evaluation tools both for the evaluation of drift of visual odometry systems and the global pose error of SLAM systems. The benchmark website [1] contains all data, detailed descriptions of the scenes, specifications of the data formats, sample code, and evaluation tools.

A Lineage of Myeloid Cells Independent of Myb and Hematopoietic Stem Cells

Abstract: Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11b(high) monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80(bright) macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia--cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

A lineage of myeloid cells independent of Myb and hematopoietic stem cells

Abstract: Macrophage Development Rewritten Macrophages provide protection against a wide variety of infections and critically shape the inflammatory environment in many tissues. These cells come in many flavors, as determined by differences in gene expression, cell surface phenotype and specific function. Schulz et al. (p. 86, published online 22 March) investigated whether adult macrophages all share a common developmental origin. Immune cells, including most macrophages, are widely thought to arise from hematopoietic stem cells (HSCs), which require the transcription factor Myb for their development. Analysis of Myb-deficient mice revealed that a population of yolk-sac–derived, tissue-resident macrophages was able to develop and persist in adult mice in the absence of HSCs. Importantly, yolk sac–derived macrophages also contributed substantially to the tissue macrophage pool even when HSCs were present. In mice, a population of tissue-resident macrophages arises independently of bone marrow–derived stem cells. Macrophages and dendritic cells (DCs) are key components of cellular immunity and are thought to originate and renew from hematopoietic stem cells (HSCs). However, some macrophages develop in the embryo before the appearance of definitive HSCs. We thus reinvestigated macrophage development. We found that the transcription factor Myb was required for development of HSCs and all CD11bhigh monocytes and macrophages, but was dispensable for yolk sac (YS) macrophages and for the development of YS-derived F4/80bright macrophages in several tissues, such as liver Kupffer cells, epidermal Langerhans cells, and microglia—cell populations that all can persist in adult mice independently of HSCs. These results define a lineage of tissue macrophages that derive from the YS and are genetically distinct from HSC progeny.

Vesiclepedia: a compendium for extracellular vesicles with continuous community annotation

Abstract: Extracellular vesicles (EVs) are membraneous vesicles released by a variety of cells into their microenvironment. Recent studies have elucidated the role of EVs in intercellular communication, pathogenesis, drug, vaccine and gene-vector delivery, and as possible reservoirs of biomarkers. These findings have generated immense interest, along with an exponential increase in molecular data pertaining to EVs. Here, we describe Vesiclepedia, a manually curated compendium of molecular data (lipid, RNA, and protein) identified in different classes of EVs from more than 300 independent studies published over the past several years. Even though databases are indispensable resources for the scientific community, recent studies have shown that more than 50% of the databases are not regularly updated. In addition, more than 20% of the database links are inactive. To prevent such database and link decay, we have initiated a continuous community annotation project with the active involvement of EV researchers. The EV research community can set a gold standard in data sharing with Vesiclepedia, which could evolve as a primary resource for the field.

Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial

Abstract: Summary Background Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. Methods Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m 2 temozolomide, given on days 1–7 of 1 week on, 1 week off cycles, or radiotherapy of 60·0 Gy, administered over 6–7 weeks in 30 fractions of 1·8–2·0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. Findings Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8·6 months (95% CI 7·3–10·2) in the temozolomide group versus 9·6 months (8·2–10·8) in the radiotherapy group (hazard ratio [HR] 1·09, 95% CI 0·84–1·42, p non-inferiority =0·033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3·3 months [95% CI 3·2–4·1] vs 4·7 [4·2–5·2]; HR 1·15, 95% CI 0·92–1·43, p non-inferiority =0·043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11·9 months [95% CI 9·0 to not reached] vs 8·2 months [7·0–10·0]; HR 0·62, 95% CI 0·42–0·91, p=0·014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8·4 months [95e% CI 5·5–11·7] vs 4·6 [4·2–5·0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3·3 months [3·0–3·5] vs 4·6 months [3·7–6·3]). The most frequent grade 3–4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). Interpretation Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. Funding Merck Sharp & Dohme.

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival

Abstract: IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells. The randomized phase 2 trial showed that a single dose of cyclophosphamide reduced the number of T(reg) cells and confirmed that immune responses to multiple TUMAPs were associated with longer overall survival. Furthermore, among six predefined populations of myeloid-derived suppressor cells, two were prognostic for overall survival, and among over 300 serum biomarkers, we identified apolipoprotein A-I (APOA1) and chemokine (C-C motif) ligand 17 (CCL17) as being predictive for both immune response to IMA901 and overall survival. A randomized phase 3 study to determine the clinical benefit of treatment with IMA901 is ongoing.

An evaluation of the RGB-D SLAM system

Abstract: We present an approach to simultaneous localization and mapping (SLAM) for RGB-D cameras like the Microsoft Kinect. Our system concurrently estimates the trajectory of a hand-held Kinect and generates a dense 3D model of the environment. We present the key features of our approach and evaluate its performance thoroughly on a recently published dataset, including a large set of sequences of different scenes with varying camera speeds and illumination conditions. In particular, we evaluate the accuracy, robustness, and processing time for three different feature descriptors (SIFT, SURF, and ORB). The experiments demonstrate that our system can robustly deal with difficult data in common indoor scenarios while being fast enough for online operation. Our system is fully available as open-source.

Review of the BCI Competition IV

Abstract: The BCI competition IV stands in the tradition of prior BCI competitions that aim to provide high quality neuroscientific data for open access to the scientific community. As experienced already in prior competitions not only scientists from the narrow field of BCI compete, but scholars with a broad variety of backgrounds and nationalities. They include high specialists as well as students. The goals of all BCI competitions have always been to challenge with respect to novel paradigms and complex data. We report on the following challenges: (1) asynchronous data, (2) synthetic, (3) multi-class continuous data, (4) session-to-session transfer, (5) directionally modulated MEG, (6) finger movements recorded by ECoG. As after past competitions, our hope is that winning entries may enhance the analysis methods of future BCIs.

The Path from β-Carotene to Carlactone, a Strigolactone-Like Plant Hormone

Abstract: Germination of parasitic witchweeds depends on strigolactones, which also regulate plant branching and signal in the context of mycorrhizal symbioses. The biosynthetic pathways that lead to strigolactones are founded in carotenoid biosynthesis, but further steps have been obscure. Alder et al. (p. [1348][1]) have now identified a biochemical pathway that generates a strigolactone-like compound, carlactone, which shows biological actions similar to those of strigolactone. [1]: /lookup/doi/10.1126/science.1218094

Thrombin-Receptor Antagonist Vorapaxar in Acute Coronary Syndromes

Abstract: In patients with acute coronary syndromes, the addition of vorapaxar to standard therapy did not significantly reduce the primary composite end point but significantly increased the risk of major bleeding, including intracranial hemorrhage. (Funded by Merck; TRACER ClinicalTrials.gov number, NCT00527943.).

B cell–helper neutrophils stimulate the diversification and production of immunoglobulin in the marginal zone of the spleen

Abstract: Follicular T cells provide help to B cells to elicit antibody responses. Cerutti and colleagues show that neutrophils provide help to marginal-zone B cells that produce T cell–independent antibodies.

UTCI--why another thermal index?

Abstract: Existing procedures for the assessment of the thermal environment in the fields of public weather services, public health systems, precautionary planning, urban design, tourism and recreation and climate impact research exhibit significant shortcomings. This is most evident for simple (mostly two-parameter) indices, when comparing them to complete heat budget models developed since the 1960s. ISB Commission 6 took up the idea of developing a Universal Thermal Climate Index (UTCI) based on the most advanced multi-node model of thermoregulation representing progress in science within the last three to four decades, both in thermo-physiological and heat exchange theory. Creating the essential research synergies for the development of UTCI required pooling the resources of multidisciplinary experts in the fields of thermal physiology, mathematical modelling, occupational medicine, meteorological data handling (in particular radiation modelling) and application development in a network. It was possible to extend the expertise of ISB Commission 6 substantially by COST (a European programme promoting Cooperation in Science and Technology) Action 730 so that finally over 45 scientists from 23 countries (Australia, Canada, Israel, several Europe countries, New Zealand, and the United States) worked together. The work was performed under the umbrella of the WMO Commission on Climatology (CCl). After extensive evaluations, Fiala’s multi-node human physiology and thermal comfort model (FPC) was adopted for this study. The model was validated extensively, applying as yet unused data from other research groups, and extended for the purposes of the project. This model was coupled with a state-of-the-art clothing model taking into consideration behavioural adaptation of clothing insulation by the general urban population in response to actual environmental temperature. UTCI was then derived conceptually as an equivalent temperature (ET). Thus, for any combination of air temperature, wind, radiation, and humidity (stress), UTCI is defined as the isothermal air temperature of the reference condition that would elicit the same dynamic response (strain) of the physiological model. As UTCI is based on contemporary science its use will standardise applications in the major fields of human biometeorology, thus making research results comparable and physiologically relevant.

Comparison of UTCI to selected thermal indices

Abstract: Over the past century more than 100 indices have been developed and used to assess bioclimatic conditions for human beings. The majority of these indices are used sporadically or for specific purposes. Some are based on generalized results of measurements (wind chill, cooling power, wet bulb temperature) and some on the empirically observed reactions of the human body to thermal stress (physiological strain, effective temperature). Those indices that are based on human heat balance considerations are referred to as "rational indices". Several simple human heat balance models are known and are used in research and practice. This paper presents a comparative analysis of the newly developed Universal Thermal Climate Index (UTCI), and some of the more prevalent thermal indices. The analysis is based on three groups of data: global data-set, synoptic datasets from Europe, and local scale data from special measurement campaigns of COST Action 730. We found the present indices to express bioclimatic conditions reasonably only under specific meteorological situations, while the UTCI represents specific climates, weather, and locations much better. Furthermore, similar to the human body, the UTCI is very sensitive to changes in ambient stimuli: temperature, solar radiation, wind and humidity. UTCI depicts temporal variability of thermal conditions better than other indices. The UTCI scale is able to express even slight differences in the intensity of meteorological stimuli.

Deriving the operational procedure for the Universal Thermal Climate Index (UTCI).

Abstract: The Universal Thermal Climate Index (UTCI) aimed for a one-dimensional quantity adequately reflecting the human physiological reaction to the multi-dimensionally defined actual outdoor thermal environment. The human reaction was simulated by the UTCI-Fiala multi-node model of human thermoregulation, which was integrated with an adaptive clothing model. Following the concept of an equivalent temperature, UTCI for a given combination of wind speed, radiation, humidity and air temperature was defined as the air temperature of the reference environment, which according to the model produces an equivalent dynamic physiological response. Operationalising this concept involved (1) the definition of a reference environment with 50% relative humidity (but vapour pressure capped at 20 hPa), with calm air and radiant temperature equalling air temperature and (2) the development of a one-dimensional representation of the multivariate model output at different exposure times. The latter was achieved by principal component analyses showing that the linear combination of 7 parameters of thermophysiological strain (core, mean and facial skin temperatures, sweat production, skin wettedness, skin blood flow, shivering) after 30 and 120 min exposure time accounted for two-thirds of the total variation in the multi-dimensional dynamic physiological response. The operational procedure was completed by a scale categorising UTCI equivalent temperature values in terms of thermal stress, and by providing simplified routines for fast but sufficiently accurate calculation, which included look-up tables of pre-calculated UTCI values for a grid of all relevant combinations of climate parameters and polynomial regression equations predicting UTCI over the same grid. The analyses of the sensitivity of UTCI to humidity, radiation and wind speed showed plausible reactions in the heat as well as in the cold, and indicate that UTCI may in this regard be universally useable in the major areas of research and application in human biometeorology.

UTCI-Fiala multi-node model of human heat transfer and temperature regulation.

Abstract: The UTCI-Fiala mathematical model of human temperature regulation forms the basis of the new Universal Thermal Climate Index (UTC). Following extensive validation tests, adaptations and extensions, such as the inclusion of an adaptive clothing model, the model was used to predict human temperature and regulatory responses for combinations of the prevailing outdoor climate conditions. This paper provides an overview of the underlying algorithms and methods that constitute the multi-node dynamic UTCI-Fiala model of human thermal physiology and comfort. Treated topics include modelling heat and mass transfer within the body, numerical techniques, modelling environmental heat exchanges, thermoregulatory reactions of the central nervous system, and perceptual responses. Other contributions of this special issue describe the validation of the UTCI-Fiala model against measured data and the development of the adaptive clothing model for outdoor climates.

Inflammatory cytokines in experimental and human stroke

Abstract: Inflammation is a hallmark of stroke pathology. The cytokines, tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, modulate tissue injury in experimental stroke and are therefore potential targets in future stroke therapy. The effect of these cytokines on infarct evolution depends on their availability in the ischemic penumbra in the early phase after stroke onset, corresponding to the therapeutic window (<4.5 hours), which is similar in human and experimental stroke. This review summarizes a large body of literature on the spatiotemporal and cellular production of TNF, IL-1, and IL-6, focusing on the early phase in experimental and human stroke. We also review studies of cytokines in blood and cerebrospinal fluid in stroke. Tumor necrosis factor and IL-1 are upregulated early in peri-infarct microglia. Newer literature suggests that IL-6 is produced by microglia, in addition to neurons. Tumor necrosis factor- and IL-1-producing macrophages infiltrate the infarct and peri-infarct with a delay. This information is discussed in the context of suggestions that neuronal sensitivity to ischemia may be modulated by cytokines. The fact that TNF and IL-1, and suppossedly also IL-6, are produced by microglia within the therapeutic window place these cells centrally in potential future stroke therapy.

New Comprehensive Cytogenetic Scoring System for Primary Myelodysplastic Syndromes (MDS) and Oligoblastic Acute Myeloid Leukemia After MDS Derived From an International Database Merge

Abstract: Purpose The karyotype is a strong independent prognostic factor in myelodysplastic syndromes (MDS). Since the implementation of the International Prognostic Scoring System (IPSS) in 1997, knowledge concerning the prognostic impact of abnormalities has increased substantially. The present study proposes a new and comprehensive cytogenetic scoring system based on an international data collection of 2,902 patients.

Correlation and process in species distribution models: bridging a dichotomy

Abstract: Within the field of species distribution modelling an apparent dichotomy exists between process-based and correlative approaches, where the processes are explicit in the former and implicit in the latter. However, these intuitive distinctions can become blurred when comparing species distribution modelling approaches in more detail. In this review article, we contrast the extremes of the correlative–process spectrum of species distribution models with respect to core assumptions, model building and selection strategies, validation, uncertainties, common errors and the questions they are most suited to answer. The extremes of such approaches differ clearly in many aspects, such as model building approaches, parameter estimation strategies and transferability. However, they also share strengths and weaknesses. We show that claims of one approach being intrinsically superior to the other are misguided and that they ignore the process–correlation continuum as well as the domains of questions that each approach is addressing. Nonetheless, the application of process-based approaches to species distribution modelling lags far behind more correlative (process-implicit) methods and more research is required to explore their potential benefits. Critical issues for the employment of species distribution modelling approaches are given, together with a guideline for appropriate usage. We close with challenges for future development of process-explicit species distribution models and how they may complement current approaches to study species distributions.

To differentiate or not — routes towards metastasis

Abstract: Why are many metastases differentiated? Invading and disseminating carcinoma cells can undergo an epithelial-mesenchymal transition (EMT), which is associated with a gain of stem cell-like behaviour. Therefore, EMT has been linked to the cancer stem cell concept. However, it is a matter of debate how subsequent mesenchymal-epithelial transition (MET) fits into the metastatic process and whether a MET is essential. In this Opinion article, I propose two principle types of metastatic progression: phenotypic plasticity involving transient EMT-MET processes and intrinsic genetic alterations keeping cells in an EMT and stemness state. This simplified classification integrates clinically relevant aspects of dormancy, metastatic tropism and therapy resistance, and implies perspectives on treatment strategies against metastasis.

European Journal of Cardio-Thoracic Surgery celebrates its 25th Anniversary: 1987–2012

Abstract: was eventually published [4] and our journal has been listed with Current

Electron performance measurements with the ATLAS detector using the 2010 LHC proton-proton collision data

Abstract: Detailed measurements of the electron performance of the ATLAS detector at the LHC are reported, using decays of the Z, W and J/psi particles. Data collected in 2010 at root s = 7 TeV are used, corresponding to an integrated luminosity of almost 40 pb(-1). The inter-alignment of the inner detector and the electromagnetic calorimeter, the determination of the electron energy scale and resolution, and the performance in terms of response uniformity and linearity are discussed. The electron identification, reconstruction and trigger efficiencies, as well as the charge misidentification probability, are also presented.

Chronic lymphocytic leukaemia is driven by antigen-independent cell-autonomous signalling

Abstract: B-cell receptor (BCR) signalling in chronic lymphocytic leukaemia (CLL) is found not to be dependent on exogenous antigens; instead, signalling may involve the binding of the BCR heavy-chain complementarity-determining region to self epitopes on the same receptor, a finding that may have important implications for understanding the pathogenesis of CLL and potential therapeutic approaches. Chronic lymphocytic leukaemia (CLL) is one of the commonest forms of leukaemia in the Western world. B-cell antigen receptor (BCR) expression is a feature of the condition, but it has been unclear whether malignancy is actually driven by BCR signalling, and hence specific antigens. Hassan Jumaa and colleagues now demonstrate that in a subset of human CLL cases, BCR signalling is important, but not dependent on exogenous antigens. Instead, activation involves the binding of one region of the BCR to self epitopes on variable regions of the same receptor. This finding has important implications for both our understanding of the pathogenesis of CLL and potential novel therapeutic approaches. B-cell antigen receptor (BCR) expression is an important feature of chronic lymphocytic leukaemia (CLL), one of the most prevalent B-cell neoplasias in Western countries1. The presence of stereotyped and quasi-identical BCRs in different CLL patients suggests that recognition of specific antigens might drive CLL pathogenesis. Here we show that, in contrast to other B-cell neoplasias, CLL-derived BCRs induce antigen-independent cell-autonomous signalling, which is dependent on the heavy-chain complementarity-determining region (HCDR3) and an internal epitope of the BCR. Indeed, transferring the HCDR3 of a CLL-derived BCR provides autonomous signalling capacity to a non-autonomously active BCR, whereas mutations in the internal epitope abolish this capacity. Because BCR expression was required for the binding of secreted CLL-derived BCRs to target cells, and mutations in the internal epitope reduced this binding, our results indicate a new model for CLL pathogenesis, with cell-autonomous antigen-independent signalling as a crucial pathogenic mechanism.

Measurement of the azimuthal anisotropy for charged particle production in √ sNN = 2.76 TeV lead-lead collisions with the ATLAS detector

Abstract: Differential measurements of charged particle azimuthal anisotropy are presented for lead-lead collisions at root sNN = 2.76 TeV with the ATLAS detector at the LHC, based on an integrated luminosity of approximately 8 mu b(-1). This anisotropy is characterized via a Fourier expansion of the distribution of charged particles in azimuthal angle relative to the reaction plane, with the coefficients v(n) denoting the magnitude of the anisotropy. Significant v(2)-v(6) values are obtained as a function of transverse momentum (0.5 = 3 are found to vary weakly with both eta and centrality, and their p(T) dependencies are found to follow an approximate scaling relation, v(n)(1/n)(p(T)) proportional to v(2)(1/2)(p(T)), except in the top 5% most central collisions. A Fourier analysis of the charged particle pair distribution in relative azimuthal angle (Delta phi = phi(a)-phi(b)) is performed to extract the coefficients v(n,n) = . For pairs of charged particles with a large pseudorapidity gap (|Delta eta = eta(a) - eta(b)| > 2) and one particle with p(T) < 3 GeV, the v(2,2)-v(6,6) values are found to factorize as v(n,n)(p(T)(a), p(T)(b)) approximate to v(n) (p(T)(a))v(n)(p(T)(b)) in central and midcentral events. Such factorization suggests that these values of v(2,2)-v(6,6) are primarily attributable to the response of the created matter to the fluctuations in the geometry of the initial state. A detailed study shows that the v(1,1)(p(T)(a), p(T)(b)) data are consistent with the combined contributions from a rapidity-even v(1) and global momentum conservation. A two-component fit is used to extract the v(1) contribution. The extracted v(1) isobserved to cross zero at pT approximate to 1.0 GeV, reaches a maximum at 4-5 GeV with a value comparable to that for v(3), and decreases at higher p(T).