315 research outputs found
Improving statistical sensitivity for fMRI data by clusterFDR
No full textIntroduction: The multiple comparison problem arises in the statistical analysis of fMRI data because independent statistical tests are performed at each voxel of an image. In order to reduce the number of tests, statistical inference is often performed at the cluster level where clusters are identified by thresholding the uncorrected map of z-values, and assuming that small clusters tend to be spurious while larger clusters are more reliable. The multiple comparison problem then still exists but is alleviated because the number of tests is reduced from many thousands to a few dozens. A common procedure is to control the 'false discovery rate' (BH-Fdr) (Benjamini and Hochberg, 1995) at the cluster level. Here we argue that BH-Fdr as implemented in major software systems (e.g. Chumbley et al 2009) is too conservative because it rests on assumptions which are unrealistic in this context. We propose a revised algorithm to solve this problem. Methods: BH-Fdr assumes that the null distribution is continuous and uniform in [0,1]. However, as we found using simulations, the distribution of cluster sizes is not uniform with small clusters being much more frequent than large ones. Thus, the corresponding null distribution is neither uniform nor continuous (fig 1,2 and Stelzer et al. 2013). To respect the specific nature of this distribution, we propose to use an empirical null density based on simulations. We employ this new null density within the framework of 'local fdr' (Efron 2007). Local fdr assumes a two-class model with a mixture density f(x) = p0 f0(x) + p1 f1(x) where f0 f1 are the null and non-null densities, and p0,p1 their priors. BH-Fdr uses the same model with f0, f1 replaced by their cumulative distributions where f0 is assumed to be uniform. In the context of fMRI, local fdr was previously proposed by Schwartzman et al (2009) for statistical inference at the voxel level. Here, we derive the empirical null by recording the sizes of randomly generated clusters and define fdr(x) = f0(x) / f(x). We call this new algorithm ``clusterFDR''. Results: We analyzed an fMRI experiment featuring an auditory paradigm described in Mueller et al (2011). In this experiment, 20 subjects (7 females) were presented with pieces of music versus scrambled music. Scanning was done at a 3T MedSpec 30/100 scanner (Bruker, Ettlingen, Germany) using a standard EPI sequence. For details see Mueller et al (2011). Using standard GLM-based data analysis, it was found that real music showed a stronger activation in left and right auditory cortices than scrambled music. Here, we also computed the reverse contrast (scrambled > real music) and found two clusters when BH-Fdr correction with an initial cluster threshold of z > 2.33 was used (figure 3). Using SPM8, spatial smoothness was found to be 6.3 voxels. We then tested clusterFDR on these data. To derive an empirical null distribution, we generated 200 images simulating zmaps with the same spatial smoothness, and obtained a histogram of cluster sizes via thresholding at z=2.33 and a null density function of corresponding p-values (figures 1,2). With our new clusterFDR, we could replicate the first finding. But in addition, we found four more clusters in the reverse contrast that had previously been overlooked (figure 3). Conclusions: As noted by Lieberman and Cunningham (2009), statistical procedures for analyzing fMRI data traditionally have been geared towards a rather strict exclusion of false positives. As a consequence, relevant aspects of the data may have been overlooked in the past (Gonzales et al 2012). Our new clusterFDR may help to remedy this problem. But let us note that statistical methodology can only be used to weed out truly random effects. It does not guard against false positives due to confounding effects
The Potential of Pulsed Low Intensity Ultrasound to stimulate Chondrocytes in a 3D Model System
No full textPhDPulsed low intensity ultrasound (PLIUS) is used clinically to accelerate fracture healing.
although the mode of action is unclear. However studies suggest that PLIUS may
stimulate endochondral ossification and consequently PLIUS may also be beneficial for
cartilage regeneration, either in vivo or as part of a tissue engineered approach. Preyious
studies using chondrocytes cultured in monolayer have suggested that PLIUS may
stimulate glycosaminoglycan (GAG) synthesis, and that calcium signalling is implicated
in this process. Therefore the present studies set out to investigate the influence of
PLIUS on bovine articular chondrocytes in monolayer and agarose culture. This
required the design of a bioreactor system which enabled cell-agarose constructs to be
subjected to PLIUS, as well as a microscope-mounted test rig enabling confocal
visualisation of intracellular calcium dynamics.
A PLIUS system and signalling characteristics were provided by Smith and Nephew,
Inc. (York, UK). Chondrocytes in agarose demonstrated a reduction in cell viability
associated with PLIUS above a spatial averaged time averaged (SAT A) intensity of
200m W /cm2
, presumably associated with transducer heating. In subsequent studies, 30
and 100mW/cm2 were applied to monolayer and agarose cultures for up to 20 days, and
biosynthesis was examined by assessment of GAG synthesis and cell proliferation using
biochemical and radio-labelling protocols. Intracellular calcium signalling was
investigated as a possible mechanotransduction pathway, using confocal mIcroscopy
and the calcium indicator Fluo-4.
In monolayer culture PLIUS did not stimulate total GAG content or cell proliferation at
either 30 or 100 mW/cm2
• In agarose cultures, PLIUS had no effect on total GAG
content at 30 mW/cm2
• At 100 mW/cm2 PLIUS induced a very small increase in total
GAG content but there was no detectable effect on the rate of GAG synthesis in either
model system at either 30 or 100 mW/cm2
. There were no PLIUS associated changes in
the levels of intracellular calcium signaling in either monolayer or agarose cultures.
Preliminary studies using Fluorescent Recovery after Photobleaching (FRAP) showed
that PLIUS at 30mW/cm2 increased diffusion of 70kDa FITC-dextrans, although this
clearly had no effect on GAG synthesis or cell proliferation.
These studies indicate that PLIUS-induced fracture healing, or any potential use of
PLIUS for cartilage repair. is unlikely to involve direct stimulation of proteoglycan
synthesis or cell proliferation. Indeed the proposed use of PLIUS in cartilage tissue
engineering is more limited than previously suggested
Polyunsaturated fatty acids in various macroalgal species from north Atlantic and tropical seas
No full textBackground - In this study the efficacy of using marine macroalgae as a source for polyunsaturated fatty acids, which are associated with the prevention of inflammation, cardiovascular diseases and mental disorders, was investigated. Methods - The fatty acid (FA) composition in lipids from seven sea weed species from the North Sea (Ulva lactuca, Chondrus crispus, Laminaria hyperborea, Fucus serratus, Undaria pinnatifida, Palmaria palmata, Ascophyllum nodosum) and two from tropical seas (Caulerpa taxifolia, Sargassum natans) was determined using GCMS. Four independent replicates were taken from each seaweed species. Results - Omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs), were in the concentration range of 2-14 mg/g dry matter (DM), while total lipid content ranged from 7-45 mg/g DM. The n-9 FAs of the selected seaweeds accounted for 3%-56% of total FAs, n-6 FAs for 3%-32% and n-3 FAs for 8%-63%. Red and brown seaweeds contain arachidonic (C20:4, n-6) and/or eicosapentaenoic acids (EPA, C20:5, n-3), the latter being an important "fish" FA, as major PUFAs while in green seaweeds these values are low and mainly C16 FAs were found. A unique observation is the presence of another typical "fish" fatty acid, docosahexaenoic acid (DHA, C22:6, n-3) at ˜ 1 mg/g DM in S. natans. The n-6: n-3 ratio is in the range of 0.05-2.75 and in most cases below 1.0. Environmental effects on lipid-bound FA composition in seaweed species are discussed. Conclusion - Marine macroalgae form a good, durable and virtually inexhaustible source for polyunsaturated fatty acids with an (n-6) FA: (n-3) FA ratio of about 1.0. This ratio is recommended by the World Health Organization to be less than 10 in order to prevent inflammatory, cardiovascular and nervous system disorders. Some marine macroalgal species, like P. palmata, contain high proportions of the "fish fatty acid" eicosapentaenoic acid (EPA, C20:5, n-3), while in S. natans also docosahexaenoic acid (DHA, C22:6, n-3) was detected
Organs from animals for man
No full textIn the following review some of the problems of xenotransplantation shall be discussed, based on the few experimental data available so far and on reports in the literature describing investigations which may be of importance for xenotransplantation. The impact of gravity on the upright posture of man versus almost all other mammals, the dysfunction between enzymes and hormones in different species and the lack of interactions between interleukins, cytokines and vasoactive substances will be taken into consideration. The question must be asked whether different levels of carrier molecules or serum proteins play a role in the physiological network. Even though the development of transgenic animals or other imaginative manipulations may lead to the acceptance of any type of xenografted organ, it has to be established for how long the products of the xenografts are able to act in the multifactorial orchestra. We are far from understanding xenogeneic molecular mechanisms involved in toxicity, necrosis and apoptosis or even reperfusion injury and ischemia in addition to the immediate mechanisms of the hyperacute xenogeneic rejection. Here, cell adhesion, blood clotting and vasomotion collide and bring micro-and macrocirculation to a standstill. All types of xenogeneic immunological mechanisms studied so far were found to have a more serious impact than those seen in allogeneic transplantation. In addition we are now only beginning to understand that so-called immunological parameters in allogeneic mechanisms act also in a true physiological manner in the xenogeneic situation. These molecular mechanisms occur behind the curtain of hyperacute, accelerated, acute or chronic xenograft rejection of which only some folds have been lifted to allow glimpses of part of the total scene. Other obstacles are likely to arise when long-term survival is achieved. These obstacles include retroviral infections, transfer of prions and severe side effects of the massive immunosuppression which will be needed. Moral, ethical and religious concerns are under debate and the species-specific production of proteins of the foreign donor species developed for clinical use suddenly appears to be a greater problem than anticipated
Arteriogenesis versus angiogenesis: similarities and differences
No full textCardiovascular diseases account for more than half of total mortality before the age of 75 in industrialized countries. To develop therapies promoting the compensatory growth of blood vessels could be superior to palliative surgical surgical interventions. Therefore, much effort has been put into investigating underlying mechanisms. Depending on the initial trigger, growth of blood vessels in adult organisms proceeds via two major processes, angiogenesis and arteriogenesis. While angiogenesis is induced by hypoxia and results in new capillaries, arteriogenesis is induced by physical forces, most importantly fluid shear stress. Consequently, chronically elevated fluid shear stress was found to be the strongest trigger under experimental conditions. Arteriogenesis describes the remodelling of pre-existing arterio-arteriolar anastomoses to completely developed and functional arteries. In both growth processes, enlargement of vascular wall structures was proposed to be covered by proliferation of existing wall cells. Recently, increasing evidence emerges, implicating a pivotal role for circulating cells, above all blood monocytes, in vascular growth processes. Since it has been shown that monocytes/macrophage release a cocktail of chemokines, growth factors and proteases involved in vascular growth, their contribution seems to be of a paracrine fashion. A similar role is currently discussed for various populations of bone-marrow derived stem cells and endothelial progenitors. In contrast, the initial hypothesis that these cells -after undergoing a (trans-)differentiation- contribute by a structural integration into the growing vessel wall, is increasingly challenged
Search for charged Higgs bosons decaying via H± → τ±ντ in the τ+jets and τ+lepton final states with 36 fb−1 of pp collision data recorded at √s = 13 TeV with the ATLAS experiment
No full textCharged Higgs bosons produced either in top-quark decays or in association
with a top-quark, subsequently decaying via H± → τ
±ντ , are searched for in 36.1 fb−1 of
proton-proton collision data at √
s = 13 TeV recorded with the ATLAS detector. Depending
on whether the top-quark produced together with H± decays hadronically or leptonically,
the search targets τ+jets and τ+lepton final states, in both cases with a hadronically
decaying τ -lepton. No evidence of a charged Higgs boson is found. For the mass range of
mH± = 90–2000 GeV, upper limits at the 95% confidence level are set on the production
cross-section of the charged Higgs boson times the branching fraction B(H± → τ
±ντ ) in
the range 4.2–0.0025 pb. In the mass range 90–160 GeV, assuming the Standard Model
cross-section for tt¯production, this corresponds to upper limits between 0.25% and 0.031%
for the branching fraction B(t → bH±) × B(H± → τ
±ντ )
Measurement of prompt photon production in √sNN=8.16 TeV p + Pb collisions with ATLAS
No full textThe inclusive production rates of isolated, prompt photons in p + Pb collisions at √sNN = 8.16 TeV
are studied with the ATLAS detector at the Large Hadron Collider using a dataset with an integrated
luminosity of 165 nb−1 recorded in 2016. The cross-section and nuclear modification factor RpPb are
measured as a function of photon transverse energy from 20 GeV to 550 GeV and in three nucleon–
nucleon centre-of-mass pseudorapidity regions, (−2.83,−2.02), (−1.84, 0.91), and (1.09, 1.90). The
cross-section and RpPb values are compared with the results of a next-to-leading-order perturbative QCD
calculation, with and without nuclear parton distribution function modifications, and with expectations
based on a model of the energy loss of partons prior to the hard scattering. The data disfavour a large
amount of energy loss and provide new constraints on the parton densities in nuclei
Dijet azimuthal correlations and conditional yields in pp and p+Pb collisions at sNN=5.02TeV with the ATLAS detector
No full textThis paper presents a measurement of forward-forward and forward-central dijet azimuthal angular correlations and conditional yields in proton-proton (pp) and proton-lead (p+Pb) collisions as a probe of the nuclear gluon density in regions where the fraction of the average momentum per nucleon carried by the parton entering the hard scattering is low. In these regions, gluon saturation can modify the rapidly increasing parton distribution function of the gluon. The analysis utilizes 25pb-1 of pp data and 360μb-1 of p+Pb data, both at sNN=5.02 TeV, collected in 2015 and 2016, respectively, with the ATLAS detector at the Large Hadron Collider. The measurement is performed in the center-of-mass frame of the nucleon-nucleon system in the rapidity range between -4.0 and 4.0 using the two highest transverse-momentum jets in each event, with the highest transverse-momentum jet restricted to the forward rapidity range. No significant broadening of azimuthal angular correlations is observed for forward-forward or forward-central dijets in p+Pb compared to pp collisions. For forward-forward jet pairs in the proton-going direction, the ratio of conditional yields in p+Pb collisions to those in pp collisions is suppressed by approximately 20%, with no significant dependence on the transverse momentum of the dijet system. No modification of conditional yields is observed for forward-central dijets
Correlated long-range mixed-harmonic fluctuations measured in pp, p+Pb and low-multiplicity Pb+Pb collisions with the ATLAS detector
No full textCorrelations of two flow harmonics vn and vm via three- and four-particle cumulants are measured in
13 TeV pp, 5.02 TeV p+Pb, and 2.76 TeV peripheral Pb+Pb collisions with the ATLAS detector at the LHC.
The goal is to understand the multi-particle nature of the long-range collective phenomenon in these
collision systems. The large non-flow background from dijet production present in the standard cumulant
method is suppressed using a method of subevent cumulants involving two, three and four subevents
separated in pseudorapidity. The results show a negative correlation between v2 and v3 and a positive
correlation between v2 and v4 for all collision systems and over the full multiplicity range. However, the
magnitudes of the correlations are found to depend on the event multiplicity, the choice of transverse
momentum range and collision system. The relative correlation strength, obtained by normalisation of
the cumulants with the v2
n from a two-particle correlation analysis, is similar in the three collision
systems and depends weakly on the event multiplicity and transverse momentum. These results based
on the subevent methods provide strong evidence of a similar long-range multi-particle collectivity in
pp, p+Pb and peripheral Pb+Pb collisions
Transverse momentum and process dependent azimuthal anisotropies in √sNN=8.16 TeV p+Pb collisions with the ATLAS detector
No full textThe azimuthal anisotropy of charged particles produced in √sNN=8.16 TeV p+Pb collisions is measured with the ATLAS detector at the LHC. The data correspond to an integrated luminosity of 165 nb−1 that was collected in 2016. Azimuthal anisotropy coefficients, elliptic v2 and triangular v3, extracted using two-particle correlations with a non-flow template fit procedure, are presented as a function of particle transverse momentum (pT) between 0.5 and 50 GeV. The v2 results are also reported as a function of centrality in three different particle pT intervals. The results are reported from minimum-bias events and jet-triggered events, where two jet pT thresholds are used. The anisotropies for particles with pT less than about 2 GeV are consistent with hydrodynamic flow expectations, while the significant non-zero anisotropies for pT in the range 9–50 GeV are not explained within current theoretical frameworks. In the pT range 2–9 GeV, the anisotropies are larger in minimum-bias than in jet-triggered events. Possible origins of these effects, such as the changing admixture of particles from hard scattering and the underlying event, are discussed
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